Silicon containing detectable compounds

ABSTRACT

Disclosed herein, inter alia, are silicon containing detectable compounds and methods of use thereof.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/673,579, filed May 18, 2018, which is incorporated herein byreference in its entirety and for all purposes.

BACKGROUND

Rhodamine and rhodol dyes are photostable with large absorptioncoefficients. The synthesis of red shifted rhodamine dyes is challengingbecause it requires building up the carbocyclic framework. Thebrightness, photostability and aqueous solubility of red rhodamines cansuffer when the carbocyclic framework is extended. Importantly, theefficiency of certain dyes is hampered by the formation ofnon-fluorescent species. Disclosed herein, inter alia, are solutions tothese and other problems in the art.

BRIEF SUMMARY

In an aspect is provided a compound, or salt thereof, having theformula:

R¹, R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, halogen, —CF₃,—CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I,—CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂,—OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R² and R³ are each independently substitutedor unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R⁸is hydrogen, a bioconjugate reactive moiety, a nucleotide, a nucleoside,or a nucleic acid. R⁹, R¹⁰, R¹¹, and R¹² are each independentlyhydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl. L¹ and L² are each independently a bond or acovalent linker. R⁴ and R⁵ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstitutedheterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁶ and R⁷substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl, or substitutedor unsubstituted heteroaryl. R⁴ and R⁹ substituents may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted heteroaryl. R⁷ and R¹⁰ substituents mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁵ and R¹¹substituents may optionally be joined to form a substituted orunsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl. R⁶ and R¹² substituents may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl.

In an aspect is provided a method of detecting the presence of an agent,wherein the agent is covalently bound to a monovalent compound asdescribed herein (e.g., wherein R⁸ reacts to form part of the covalentlinker), wherein the agent is an oligonucleotide, protein, or acompound.

In another aspect is provided a method of making a compound, or saltthereof, having the formula:

the method including mixing compound A, compound B, and compound C in areaction vessel. Compound A has the formula:

Compound B is a coupling reagent. Compound C has the formula:

R¹, R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, halogen, —CF₃,—CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I,—CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂,—OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. R² and R³ are each independently substitutedor unsubstituted alkyl, or substituted or unsubstituted heteroalkyl. R⁸is hydrogen, a bioconjugate reactive moiety, a nucleotide, a nucleoside,or a nucleic acid. R⁹, R¹⁰, R¹¹, and R¹², are each independentlyhydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl. R¹³ is a leaving group (e.g., hydrogen). L¹and L² are each independently a bond or a covalent linker. R⁴ and R⁵substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl, or substitutedor unsubstituted heteroaryl. R⁶ and R⁷ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl. R⁴ and R⁹ substituents may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl. R⁷ and R¹⁰ substituents may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted heteroaryl. R⁵ and R¹¹ substituents mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl, or substituted or unsubstituted heteroaryl. R⁶ and R¹²substituents may optionally be joined to form a substituted orunsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1E. Non-limiting examples of Si-rhodamine dyes synthesizedaccording to the methods described herein.

FIG. 2 . Equilibrium between the fluorescent, ring-opened form andnon-fluorescent, spirolactone form of siTMR.

DETAILED DESCRIPTION I. Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchedcarbon chain (or carbon), or combination thereof, which may be fullysaturated, mono- or polyunsaturated and can include mono-, di-, andmultivalent radicals. The alkyl may include a designated number ofcarbons (e.g., C₁-C₁₀ means one to ten carbons). Alkyl is an uncyclizedchain. Examples of saturated hydrocarbon radicals include, but are notlimited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl,t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, forexample, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. Anunsaturated alkyl group is one having one or more double bonds or triplebonds. Examples of unsaturated alkyl groups include, but are not limitedto, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl),2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl,3-butynyl, and the higher homologs and isomers. An alkoxy is an alkylattached to the remainder of the molecule via an oxygen linker (—O—). Analkyl moiety may be an alkenyl moiety. An alkyl moiety may be an alkynylmoiety. An alkyl moiety may be fully saturated. An alkenyl may includemore than one double bond and/or one or more triple bonds in addition tothe one or more double bonds. An alkynyl may include more than onetriple bond and/or one or more double bonds in addition to the one ormore triple bonds.

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred herein. A “lower alkyl”or “lower alkylene” is a shorter chain alkyl or alkylene group,generally having eight or fewer carbon atoms. The term “alkenylene,” byitself or as part of another substituent, means, unless otherwisestated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable straight or branched chain, orcombinations thereof, including at least one carbon atom and at leastone heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen andsulfur atoms may optionally be oxidized, and the nitrogen heteroatom mayoptionally be quaternized. The heteroatom(s) (e.g., O, N, S, Si, or P)may be placed at any interior position of the heteroalkyl group or atthe position at which the alkyl group is attached to the remainder ofthe molecule. Heteroalkyl is an uncyclized chain. Examples include, butare not limited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃,—CH₂—CH₂—N(CH₃)—CH₃, —CH₂—S—CH₂—CH₃, —CH₂—S—CH₂, —S(O)—CH₃,—CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃, —Si(CH₃)₃, —CH₂—CH═N—OCH₃,—CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and —CN. Up to two or threeheteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃ and—CH₂—O—Si(CH₃)₃. A heteroalkyl moiety may include one heteroatom (e.g.,O, N, S, Si, or P). A heteroalkyl moiety may include two optionallydifferent heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moietymay include three optionally different heteroatoms (e.g., O, N, S, Si,or P). A heteroalkyl moiety may include four optionally differentheteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may includefive optionally different heteroatoms (e.g., O, N, S, Si, or P). Aheteroalkyl moiety may include up to 8 optionally different heteroatoms(e.g., O, N, S, Si, or P). The term “heteroalkenyl,” by itself or incombination with another term, means, unless otherwise stated, aheteroalkyl including at least one double bond. A heteroalkenyl mayoptionally include more than one double bond and/or one or more triplebonds in additional to the one or more double bonds. The term“heteroalkynyl,” by itself or in combination with another term, means,unless otherwise stated, a heteroalkyl including at least one triplebond. A heteroalkynyl may optionally include more than one triple bondand/or one or more double bonds in additional to the one or more triplebonds.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicversions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl andheterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or amulticyclic cycloalkyl ring system. In embodiments, monocyclic ringsystems are cyclic hydrocarbon groups containing from 3 to 8 carbonatoms, where such groups can be saturated or unsaturated, but notaromatic. In embodiments, cycloalkyl groups are fully saturated.Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclicrings or fused bicyclic rings. In embodiments, bridged monocyclic ringscontain a monocyclic cycloalkyl ring where two non adjacent carbon atomsof the monocyclic ring are linked by an alkylene bridge of between oneand three additional carbon atoms (i.e., a bridging group of the form(CH₂)_(w), where w is 1, 2, or 3). Representative examples of bicyclicring systems include, but are not limited to, bicyclo[3.1.1]heptane,bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane,bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. In embodiments, fusedbicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ringfused to either a phenyl, a monocyclic cycloalkyl, a monocycliccycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. Inembodiments, the bridged or fused bicyclic cycloalkyl is attached to theparent molecular moiety through any carbon atom contained within themonocyclic cycloalkyl ring. In embodiments, cycloalkyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In embodiments, the fused bicyclic cycloalkyl is a 5 or 6membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocycliccycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl isoptionally substituted by one or two groups which are independently oxoor thia. In embodiments, multicyclic cycloalkyl ring systems are amonocyclic cycloalkyl ring (base ring) fused to either (i) one ringsystem selected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other ring systems independentlyselected from the group consisting of a phenyl, a bicyclic aryl, amonocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl,a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclicheterocyclyl. In embodiments, the multicyclic cycloalkyl is attached tothe parent molecular moiety through any carbon atom contained within thebase ring. In embodiments, multicyclic cycloalkyl ring systems are amonocyclic cycloalkyl ring (base ring) fused to either (i) one ringsystem selected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other ring systems independentlyselected from the group consisting of a phenyl, a monocyclic heteroaryl,a monocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclicheterocyclyl. Examples of multicyclic cycloalkyl groups include, but arenot limited to tetradecahydrophenanthrenyl, perhydrophenothiazin-1-yl,and perhydrophenoxazin-1-yl.

In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl”is used in accordance with its plain ordinary meaning. In embodiments, acycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenylring system. In embodiments, monocyclic cycloalkenyl ring systems arecyclic hydrocarbon groups containing from 3 to 8 carbon atoms, wheresuch groups are unsaturated (i.e., containing at least one annularcarbon carbon double bond), but not aromatic. Examples of monocycliccycloalkenyl ring systems include cyclopentenyl and cyclohexenyl. Inembodiments, bicyclic cycloalkenyl rings are bridged monocyclic rings ora fused bicyclic rings. In embodiments, bridged monocyclic rings containa monocyclic cycloalkenyl ring where two non adjacent carbon atoms ofthe monocyclic ring are linked by an alkylene bridge of between one andthree additional carbon atoms (i.e., a bridging group of the form(CH₂)_(w), where w is 1, 2, or 3). Representative examples of bicycliccycloalkenyls include, but are not limited to, norbornenyl andbicyclo[2.2.2]oct 2 enyl. In embodiments, fused bicyclic cycloalkenylring systems contain a monocyclic cycloalkenyl ring fused to either aphenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocyclyl, or a monocyclic heteroaryl. In embodiments, the bridged orfused bicyclic cycloalkenyl is attached to the parent molecular moietythrough any carbon atom contained within the monocyclic cycloalkenylring. In embodiments, cycloalkenyl groups are optionally substitutedwith one or two groups which are independently oxo or thia. Inembodiments, multicyclic cycloalkenyl rings contain a monocycliccycloalkenyl ring (base ring) fused to either (i) one ring systemselected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two ring systems independently selectedfrom the group consisting of a phenyl, a bicyclic aryl, a monocyclic orbicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl, a monocyclicor bicyclic cycloalkenyl, and a monocyclic or bicyclic heterocyclyl. Inembodiments, the multicyclic cycloalkenyl is attached to the parentmolecular moiety through any carbon atom contained within the base ring.In embodiments, multicyclic cycloalkenyl rings contain a monocycliccycloalkenyl ring (base ring) fused to either (i) one ring systemselected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two ring systems independently selectedfrom the group consisting of a phenyl, a monocyclic heteroaryl, amonocyclic cycloalkyl, a monocyclic cycloalkenyl, and a monocyclicheterocyclyl.

In embodiments, a heterocycloalkyl is a heterocyclyl. The term“heterocyclyl” as used herein, means a monocyclic, bicyclic, ormulticyclic heterocycle. The heterocyclyl monocyclic heterocycle is a 3,4, 5, 6 or 7 membered ring containing at least one heteroatomindependently selected from the group consisting of O, N, and S wherethe ring is saturated or unsaturated, but not aromatic. The 3 or 4membered ring contains 1 heteroatom selected from the group consistingof O, N and S. The 5 membered ring can contain zero or one double bondand one, two or three heteroatoms selected from the group consisting ofO, N and S. The 6 or 7 membered ring contains zero, one or two doublebonds and one, two or three heteroatoms selected from the groupconsisting of O, N and S. The heterocyclyl monocyclic heterocycle isconnected to the parent molecular moiety through any carbon atom or anynitrogen atom contained within the heterocyclyl monocyclic heterocycle.Representative examples of heterocyclyl monocyclic heterocycles include,but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl,1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl,imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl,isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl,oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl,pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl,tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl,thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The heterocyclylbicyclic heterocycle is a monocyclic heterocycle fused to either aphenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocycle, or a monocyclic heteroaryl. The heterocyclyl bicyclicheterocycle is connected to the parent molecular moiety through anycarbon atom or any nitrogen atom contained within the monocyclicheterocycle portion of the bicyclic ring system. Representative examplesof bicyclic heterocyclyls include, but are not limited to,2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl,indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl,decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, andoctahydrobenzofuranyl. In embodiments, heterocyclyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or6 membered monocyclic heterocyclyl ring fused to a phenyl ring, a 5 or 6membered monocyclic cycloalkyl, a 5 or 6 membered monocycliccycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl isoptionally substituted by one or two groups which are independently oxoor thia. Multicyclic heterocyclyl ring systems are a monocyclicheterocyclyl ring (base ring) fused to either (i) one ring systemselected from the group consisting of a bicyclic aryl, a bicyclicheteroaryl, a bicyclic cycloalkyl, a bicyclic cycloalkenyl, and abicyclic heterocyclyl; or (ii) two other ring systems independentlyselected from the group consisting of a phenyl, a bicyclic aryl, amonocyclic or bicyclic heteroaryl, a monocyclic or bicyclic cycloalkyl,a monocyclic or bicyclic cycloalkenyl, and a monocyclic or bicyclicheterocyclyl. The multicyclic heterocyclyl is attached to the parentmolecular moiety through any carbon atom or nitrogen atom containedwithin the base ring. In embodiments, multicyclic heterocyclyl ringsystems are a monocyclic heterocyclyl ring (base ring) fused to either(i) one ring system selected from the group consisting of a bicyclicaryl, a bicyclic heteroaryl, a bicyclic cycloalkyl, a bicycliccycloalkenyl, and a bicyclic heterocyclyl; or (ii) two other ringsystems independently selected from the group consisting of a phenyl, amonocyclic heteroaryl, a monocyclic cycloalkyl, a monocycliccycloalkenyl, and a monocyclic heterocyclyl. Examples of multicyclicheterocyclyl groups include, but are not limited to10H-phenothiazin-10-yl, 9,10-dihydroacridin-9-yl,9,10-dihydroacridin-10-yl, 10H-phenoxazin-10-yl,10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl,1,2,3,4-tetrahydropyrido[4,3-g]isoquinolin-2-yl,12H-benzo[b]phenoxazin-12-yl, and dodecahydro-1H-carbazol-9-yl.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently. A fused ring aryl refersto multiple rings fused together wherein at least one of the fused ringsis an aryl ring. The term “heteroaryl” refers to aryl groups (or rings)that contain at least one heteroatom such as N, O, or S, wherein thenitrogen and sulfur atoms are optionally oxidized, and the nitrogenatom(s) are optionally quaternized. Thus, the term “heteroaryl” includesfused ring heteroaryl groups (i.e., multiple rings fused togetherwherein at least one of the fused rings is a heteroaromatic ring). A5,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 5 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. Likewise, a 6,6-fused ringheteroarylene refers to two rings fused together, wherein one ring has 6members and the other ring has 6 members, and wherein at least one ringis a heteroaryl ring. And a 6,5-fused ring heteroarylene refers to tworings fused together, wherein one ring has 6 members and the other ringhas 5 members, and wherein at least one ring is a heteroaryl ring. Aheteroaryl group can be attached to the remainder of the moleculethrough a carbon or heteroatom. Non-limiting examples of aryl andheteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl,pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl,oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl,benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl,indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl,quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl,3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl,2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl,4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl,5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. An “arylene” and a“heteroarylene,” alone or as part of another substituent, mean adivalent radical derived from an aryl and heteroaryl, respectively. Aheteroaryl group substituent may be —O— bonded to a ring heteroatomnitrogen.

Spirocyclic rings are two or more rings wherein adjacent rings areattached through a single atom. The individual rings within spirocyclicrings may be identical or different. Individual rings in spirocyclicrings may be substituted or unsubstituted and may have differentsubstituents from other individual rings within a set of spirocyclicrings. Possible substituents for individual rings within spirocyclicrings are the possible substituents for the same ring when not part ofspirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkylrings). Spirocylic rings may be substituted or unsubstituted cycloalkyl,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkyl or substituted or unsubstituted heterocycloalkylene andindividual rings within a spirocyclic ring group may be any of theimmediately previous list, including having all rings of one type (e.g.,all rings being substituted heterocycloalkylene wherein each ring may bethe same or different substituted heterocycloalkylene). When referringto a spirocyclic ring system, heterocyclic spirocyclic rings means aspirocyclic rings wherein at least one ring is a heterocyclic ring andwherein each ring may be a different ring. When referring to aspirocyclic ring system, substituted spirocyclic rings means that atleast one ring is substituted and each substituent may optionally bedifferent.

The symbol “

” denotes the point of attachment of a chemical moiety to the

remainder of a molecule or chemical formula.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylarylene” as an arylene moiety covalently bonded to analkylene moiety (also referred to herein as an alkylene linker). Inembodiments, the alkylarylene group has the formula:

An alkylarylene moiety may be substituted (e.g., with a substituentgroup) on the alkylene moiety or the arylene linker (e.g., at carbons 2,3, 4, or 6) with halogen, oxo, —N₃, —CF₃, —CCl₃, —CBr₃, —CI₃, —CN, —CHO,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂CH₃—SO₃H, —OSO₃H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC(O)NHNH₂, substituted or unsubstituted C₁-C₅ alkyl orsubstituted or unsubstituted 2 to 5 membered heteroalkyl). Inembodiments, the alkylarylene is unsubstituted.

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,”“heterocycloalkyl,” “aryl,” and “heteroaryl”) includes both substitutedand unsubstituted forms of the indicated radical. Preferred substituentsfor each type of radical are provided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″,—NR—C(NR′R″)═NR′″, —S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″,—ONR′R″, —NR′C(O)NR″NR′″R″″, —CN, —NO₂, —NR′SO₂R″, —NR′C(O)R″,—NR′C(O)—OR″, —NR′OR″, in a number ranging from zero to (2m′+1), wherem′ is the total number of carbon atoms in such radical. R, R′, R″, R′″,and R″″ each preferably independently refer to hydrogen, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl (e.g., aryl substituted with 1-3 halogens),substituted or unsubstituted heteroaryl, substituted or unsubstitutedalkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups. When acompound described herein includes more than one R group, for example,each of the R groups is independently selected as are each R′, R″, R′″,and R″″ group when more than one of these groups is present. When R′ andR″ are attached to the same nitrogen atom, they can be combined with thenitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example,—NR′R″ includes, but is not limited to, 1-pyrrolidinyl and4-morpholinyl. From the above discussion of substituents, one of skillin the art will understand that the term “alkyl” is meant to includegroups including carbon atoms bound to groups other than hydrogengroups, such as haloalkyl (e.g., —CF₃ and —CH₂CF₃) and acyl (e.g.,—C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and the like).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″,—NR′C(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, —NR′SO₂R″, —NR′C(O)R″, —NR′C(O)—OR″, —NR′OR″, ina number ranging from zero to the total number of open valences on thearomatic ring system; and where R′, R″, R′″, and R″″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl. When a compound described herein includes more than one Rgroup, for example, each of the R groups is independently selected asare each R′, R″, R′″, and R″″ groups when more than one of these groupsis present.

Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl,heteroaryl, cycloalkylene, heterocycloalkylene, arylene, orheteroarylene) may be depicted as substituents on the ring rather thanon a specific atom of a ring (commonly referred to as a floatingsubstituent). In such a case, the substituent may be attached to any ofthe ring atoms (obeying the rules of chemical valency) and in the caseof fused rings or spirocyclic rings, a substituent depicted asassociated with one member of the fused rings or spirocyclic rings (afloating substituent on a single ring), may be a substituent on any ofthe fused rings or spirocyclic rings (a floating substituent on multiplerings). When a substituent is attached to a ring, but not a specificatom (a floating substituent), and a subscript for the substituent is aninteger greater than one, the multiple substituents may be on the sameatom, same ring, different atoms, different fused rings, differentspirocyclic rings, and each substituent may optionally be different.Where a point of attachment of a ring to the remainder of a molecule isnot limited to a single atom (a floating substituent), the attachmentpoint may be any atom of the ring and in the case of a fused ring orspirocyclic ring, any atom of any of the fused rings or spirocyclicrings while obeying the rules of chemical valency. Where a ring, fusedrings, or spirocyclic rings contain one or more ring heteroatoms and thering, fused rings, or spirocyclic rings are shown with one more floatingsubstituents (including, but not limited to, points of attachment to theremainder of the molecule), the floating substituents may be bonded tothe heteroatoms. Where the ring heteroatoms are shown bound to one ormore hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and athird bond to a hydrogen) in the structure or formula with the floatingsubstituent, when the heteroatom is bonded to the floating substituent,the substituent will be understood to replace the hydrogen, whileobeying the rules of chemical valency.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl, —CH₂Br,        —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂,        —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,        —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,        —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂,        —PO₃H, —PO₄H, —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆        alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g., 2 to 8        membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4        membered heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈        cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),        unsubstituted heterocycloalkyl (e.g., 3 to 8 membered        heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6        membered heterocycloalkyl), unsubstituted aryl (e.g., C₆-C₁₀        aryl, C₁₀ aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5        to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6        membered heteroaryl), and    -   (B) alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),        heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered        heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g.,        C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),        heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6        membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),        aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), heteroaryl (e.g.,        5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to        6 membered heteroaryl), substituted with at least one        substituent selected from:        -   (i) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl, —CH₂Br,            —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH, —NH₂,            —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,            —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H,            —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,            —OCHBr₂, —OCHI₂, —OCHF₂, —PO₃H, —PO₄H, —N₃, unsubstituted            alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),            unsubstituted heteroalkyl (e.g., 2 to 8 membered            heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered            heteroalkyl), unsubstituted cycloalkyl (e.g., C₃-C₈            cycloalkyl, C₃-C₆ cycloalkyl, or C₅-C₆ cycloalkyl),            unsubstituted heterocycloalkyl (e.g., 3 to 8 membered            heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to            6 membered heterocycloalkyl), unsubstituted aryl (e.g.,            C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or unsubstituted            heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9            membered heteroaryl, or 5 to 6 membered heteroaryl), and        -   (ii) alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄ alkyl),            heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6            membered heteroalkyl, or 2 to 4 membered heteroalkyl),            cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆ cycloalkyl, or            C₅-C₆ cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered            heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to            6 membered heterocycloalkyl), aryl (e.g., C₆-C₁₀ aryl, C₁₀            aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered            heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered            heteroaryl), substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl,                —CH₂Br, —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN,                —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,                —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂,                —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃,                —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —PO₃H,                —PO₄H, —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl,                C₁-C₆ alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl                (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered                heteroalkyl, or 2 to 4 membered heteroalkyl),                unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆                cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted                heterocycloalkyl (e.g., 3 to 8 membered                heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5                to 6 membered heterocycloalkyl), unsubstituted aryl                (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or                unsubstituted heteroaryl (e.g., 5 to 10 membered                heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6                membered heteroaryl), and            -   (b) alkyl (e.g., C₁-C₈ alkyl, C₁-C₆ alkyl, or C₁-C₄                alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl,                2 to 6 membered heteroalkyl, or 2 to 4 membered                heteroalkyl), cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆                cycloalkyl, or C₅-C₆ cycloalkyl), heterocycloalkyl                (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered                heterocycloalkyl, or 5 to 6 membered heterocycloalkyl),                aryl (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl),                heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9                membered heteroaryl, or 5 to 6 membered heteroaryl),                substituted with at least one substituent selected from:                oxo, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CH₂Cl, —CH₂Br,                —CH₂F, —CH₂I, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CN, —OH,                —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,                —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,                —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃,                —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —PO₃H, —PO₄H,                —N₃, unsubstituted alkyl (e.g., C₁-C₈ alkyl, C₁-C₆                alkyl, or C₁-C₄ alkyl), unsubstituted heteroalkyl (e.g.,                2 to 8 membered heteroalkyl, 2 to 6 membered                heteroalkyl, or 2 to 4 membered heteroalkyl),                unsubstituted cycloalkyl (e.g., C₃-C₈ cycloalkyl, C₃-C₆                cycloalkyl, or C₅-C₆ cycloalkyl), unsubstituted                heterocycloalkyl (e.g., 3 to 8 membered                heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5                to 6 membered heterocycloalkyl), unsubstituted aryl                (e.g., C₆-C₁₀ aryl, C₁₀ aryl, or phenyl), or                unsubstituted heteroaryl (e.g., 5 to 10 membered                heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6                membered heteroaryl).

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound (e.g., nucleotide analogue) is a chemicalspecies set forth in the Examples section, claims, embodiments, figures,or tables below.

In embodiments, a substituted or unsubstituted moiety (e.g., substitutedor unsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, and/orsubstituted or unsubstituted heteroarylene) is unsubstituted (e.g., isan unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl,unsubstituted heteroaryl, unsubstituted alkylene, unsubstitutedheteroalkylene, unsubstituted cycloalkylene, unsubstitutedheterocycloalkylene, unsubstituted arylene, and/or unsubstitutedheteroarylene, respectively). In embodiments, a substituted orunsubstituted moiety (e.g., substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, and/or substituted or unsubstituted heteroarylene) issubstituted (e.g., is a substituted alkyl, substituted heteroalkyl,substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl,substituted heteroaryl, substituted alkylene, substitutedheteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene, respectively).

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one substituent group,wherein if the substituted moiety is substituted with a plurality ofsubstituent groups, each substituent group may optionally be different.In embodiments, if the substituted moiety is substituted with aplurality of substituent groups, each substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one size-limited substituentgroup, wherein if the substituted moiety is substituted with a pluralityof size-limited substituent groups, each size-limited substituent groupmay optionally be different. In embodiments, if the substituted moietyis substituted with a plurality of size-limited substituent groups, eachsize-limited substituent group is different.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one lower substituent group,wherein if the substituted moiety is substituted with a plurality oflower substituent groups, each lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of lower substituent groups, each lower substituent group isdifferent.

In embodiments, a substituted moiety (e.g., substituted alkyl,substituted heteroalkyl, substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl, substituted heteroaryl, substitutedalkylene, substituted heteroalkylene, substituted cycloalkylene,substituted heterocycloalkylene, substituted arylene, and/or substitutedheteroarylene) is substituted with at least one substituent group,size-limited substituent group, or lower substituent group; wherein ifthe substituted moiety is substituted with a plurality of groupsselected from substituent groups, size-limited substituent groups, andlower substituent groups; each substituent group, size-limitedsubstituent group, and/or lower substituent group may optionally bedifferent. In embodiments, if the substituted moiety is substituted witha plurality of groups selected from substituent groups, size-limitedsubstituent groups, and lower substituent groups; each substituentgroup, size-limited substituent group, and/or lower substituent group isdifferent.

Where a moiety is substituted (e.g., substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene), the moiety is substituted with at least one substituent(e.g., a substituent group, a size-limited substituent group, or lowersubstituent group) and each substituent is optionally different.Additionally, where multiple substituents are present on a moiety, eachsubstituent may be optionally different.

In a recited claim or chemical formula description herein, each Rsubstituent or L linker that is described as being “substituted” withoutreference as to the identity of any chemical moiety that composes the“substituted” group (also referred to herein as an “open substitution”on a R substituent or L linker or an “openly substituted” R substituentor L linker), the recited R substituent or L linker may, in embodiments,be substituted with one or more “first substituent group(s)” as definedbelow.

The first substituent group is denoted with a corresponding firstdecimal point numbering system such that, for example, R¹ may besubstituted with one or more first substituent groups denoted byR^(1.1), R² may be substituted with one or more first substituent groupsdenoted by R^(2.1), R³ may be substituted with one or more firstsubstituent groups denoted by R^(3.1), R⁴ may be substituted with one ormore first substituent groups denoted by R^(4.1), R⁵ may be substitutedwith one or more first substituent groups denoted by R^(5.1), and thelike up to or exceeding an R¹⁰⁰ that may be substituted with one or morefirst substituent groups denoted by R^(100.1). As a further example,R^(1A) may be substituted with one or more first substituent groupsdenoted by R^(1A.1), R^(2A) may be substituted with one or more firstsubstituent groups denoted by R^(2A.1), R^(3A) may be substituted withone or more first substituent groups denoted by R^(3A.1), R^(4A) may besubstituted with one or more first substituent groups denoted byR^(4A.1), R^(5A) may be substituted with one or more first substituentgroups denoted by R^(5A.1) and the like up to or exceeding an R^(100A)may be substituted with one or more first substituent groups denoted byR^(100A.1). As a further example, L¹ may be substituted with one or morefirst substituent groups denoted by R^(L1.1), L² may be substituted withone or more first substituent groups denoted by R^(L2.1), L³ may besubstituted with one or more first substituent groups denoted byR^(L3.1) L⁴ may be substituted with one or more first substituent groupsdenoted by R^(L4.1), L⁵ may be substituted with one or more firstsubstituent groups denoted by R^(L5.1) and the like up to or exceedingan L¹⁰⁰ which may be substituted with one or more first substituentgroups denoted by R^(L100.1). Thus, each numbered R group or L group(alternatively referred to herein as R^(WW) or L^(WW) wherein “WW”represents the stated superscript number of the subject R group or Lgroup) described herein may be substituted with one or more firstsubstituent groups referred to herein generally as R^(WW.1) orR^(LWW.1), respectively. In turn, each first substituent group (e.g.,R^(1.1), R^(2.1), R^(3.1), R^(4.1), R^(5.1) . . . R^(100.1); R^(1A.1),R^(2A.1), R^(3A.1), R^(4A.1), R^(5A.1) . . . R^(100A.1); R^(L1.1),R^(L2.1), R^(L3.1), R^(L4.1), R^(L5.1) . . . R^(L100.1)) may be furthersubstituted with one or more second substituent groups (e.g., R^(1.2),R^(2.2), R^(3.2), R^(4.2), R^(5.2) . . . R^(100.2); R^(1A.2), R^(2A.2),R^(3A.2), R^(4A.2), R^(5A.2) . . . R^(100A.2); R^(L1.2), R^(L2.2),R^(L3.2), R^(L4.2), R^(L5.2) . . . R^(L100.2), respectively). Thus, eachfirst substituent group, which may alternatively be represented hereinas R^(WW.1) as described above, may be further substituted with one ormore second substituent groups, which may alternatively be representedherein as R^(WW.2).

Finally, each second substituent group (e.g., R^(1.2), R^(2.2), R^(3.2),R^(4.2), R^(5.2), . . . R^(100.2); R^(1A.2), R^(2A.2), R^(3A.2),R^(4A.2), R^(5A.2) . . . R^(100A.2); R^(L1.2), R^(L2.2), R^(L3.2),R^(L4.2), R^(L5.2) . . . R^(L100.2)) may be further substituted with oneor more third substituent groups (e.g., R^(1.3), R^(2.3), R^(3.3),R^(4.3), R^(5.3) . . . . R^(100.3); R^(1A.3), R^(2A.3), R^(3A.3),R^(4A.3), R^(5A.3) . . . R^(100A.3); R^(L1.3), R^(L2.3), R^(L3.3),R^(L4.3), R^(L5.3) . . . R^(L100.3); respectively). Thus, each secondsubstituent group, which may alternatively be represented herein asR^(WW.2) as described above, may be further substituted with one or morethird substituent groups, which may alternatively be represented hereinas R^(WW.3). Each of the first substituent groups may be optionallydifferent. Each of the second substituent groups may be optionallydifferent. Each of the third substituent groups may be optionallydifferent.

Thus, as used herein, R^(WW) represents a substituent recited in a claimor chemical formula description herein, which is openly substituted.“WW” represents the stated superscript number of the subject R group(e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). Likewise, L^(WW) is alinker recited in a claim or chemical formula description herein whichis openly substituted. Again, “WW” represents the stated superscriptnumber of the subject L group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B,etc.). As stated above, in embodiments, each R^(WW) may be unsubstitutedor independently substituted with one or more first substituent groups,referred to herein as R^(WW.1); each first substituent group, R^(WW.1),may be unsubstituted or independently substituted with one or moresecond substituent groups, referred to herein as R^(WW.2); and eachsecond substituent group may be unsubstituted or independentlysubstituted with one or more third substituent groups, referred toherein as R^(WW.3). Similarly, each L^(WW) linker may be unsubstitutedor independently substituted with one or more first substituent groups,referred to herein as R^(LWW.1); each first substituent group,R^(LWW.1), may be unsubstituted or independently substituted with one ormore second substituent groups, referred to herein as R^(LWW.2); andeach second substituent group may be unsubstituted or independentlysubstituted with one or more third substituent groups, referred toherein as R^(LWW.3). Each first substituent group is optionallydifferent. Each second substituent group is optionally different. Eachthird substituent group is optionally different.

R^(WW.1) is independently oxo, halogen, —CX^(WW.1) ₃, —CHX^(WW.1) ₂,—CH₂X^(WW.1), —OCX^(WW.1) ₃, —OCH₂X^(WW.1), —OCHX^(WW.1) ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃,R^(WW.2)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(WW.2)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(WW.2)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(WW.2)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(WW.2)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(WW.2)-substituted or unsubstituted heteroaryl (e.g., 5 to 12membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R^(WW.1) is independently oxo, halogen, —CX^(WW.1) ₃,—CHX^(WW.1) ₂, —CH₂X^(WW.1), —OCX^(WW.1) ₃, —OCH₂X^(WW.1), —OCHX^(WW.1)₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)—OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(WW.1) is independently —F, —Cl, —Br, or —I.

R^(WW.2) is independently oxo, halogen, —CX^(WW.2) ₃, —CHX^(WW.2) ₂,—CH₂X^(WW.2), —OCX^(WW.2) ₃, —OCH₂X^(WW.2), —OCHX^(WW.2) ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃,R^(WW.3)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(WW.3)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(WW.3)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(WW.3)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(WW.3)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(WW.3)-substituted or unsubstituted heteroaryl (e.g., 5 to 12membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R^(WW.2) is independently oxo, halogen, —CX^(WW.2) ₃,—CHX^(WW.2) ₂, —CH₂X^(WW.2), —OCX^(WW.2) ₃, —OCH₂X^(WW.2), —OCHX^(WW.2)₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(WW.2) is independently —F, —Cl, —Br, or —I.

R^(WW.3) is independently oxo, halogen, —CX^(WW.3) ₃, —CHX^(WW.3) ₂,—CH₂X^(WW.3), —OCX^(WW.3) ₃, —OCH₂X^(WW.3), —OCHX^(WW.3) ₂, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orunsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). X^(WW.3) is independently —F, —Cl, —Br,or —I.

Where two different R^(WW) substituents are joined together to form anopenly substituted ring (e.g., substituted cycloalkyl, substitutedheterocycloalkyl, substituted aryl or substituted heteroaryl), inembodiments, the openly substituted ring may be independentlysubstituted with one or more first substituent groups, referred toherein as R^(WW.1); each first substituent group, R^(WW.1), may beunsubstituted or independently substituted with one or more secondsubstituent groups, referred to herein as R^(WW.2); and each secondsubstituent group, R^(WW.2), may be unsubstituted or independentlysubstituted with one or more third substituent groups, referred toherein as R^(WW.3); and each third substituent group, R^(WW.3), isunsubstituted. Each first ring substituent group is optionallydifferent. Each second ring substituent group is optionally different.Each third ring substituent group is optionally different. In thecontext of two different R^(WW) substituents joined together to form anopenly substituted ring, the “WW” symbol in the R^(WW.1), R^(WW.2), andR^(WW.3) refers to the designated number of one of the two differentR^(WW) substituents. For example, in embodiments where R^(100A) andR^(100B) are optionally joined together to form an openly substitutedring, R^(WW.1) is R^(100A.1), R^(WW.2) is R^(100A.2), and R^(WW.3) isR^(100A.3). Alternatively, in embodiments where R^(100A) and R^(100B)are optionally joined together to form an openly substituted ring,R^(WW.1) is R^(100B.1), R^(WW.2) is R^(100B.2), and R^(WW.3) isR^(100B3). R^(WW.1), R^(WW.2), and R^(WW.3) in this paragraph are asdefined in the preceding paragraphs.

R^(LWW.1) is independently oxo, halogen, —CX^(LWW.1) ₃, —CHX^(LWW.1) ₂,—CH₂X^(LWW.1), —OCX^(LWW.1) ₃, —OCH₂X^(LWW.1), —OCHX^(LWW.1) ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—N₃, R^(LWW.2)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R^(LWW.2)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3membered, or 4 to 5 membered), R^(LWW.2)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(LWW.2)-substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R^(LWW.2)-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or R^(LWW.2)-substituted or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).In embodiments, R^(LWW.1) is independently oxo, halogen, —CX^(LWW.1) ₃,—CHX^(LWW.1) ₂, —CH₂X^(LWW.1), —OCX^(LWW.1) ₃, —OCH₂X^(LWW.1),—OCHX^(LWW.1) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(LWW.1) is independently —F, —Cl, —Br, or —I.

R^(LWW.2) is independently oxo, halogen, —CX^(LWW.2) ₃, —CHX^(LWW.2) ₂,—CH₂X^(LWW.2), —OCX^(LWW.2) ₃, —OCH₂X^(LWW.2), —OCHX^(LWW.2) ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—N₃, R^(LWW.3)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R^(LWW.3)-substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3membered, or 4 to 5 membered), R^(WW.3)-substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(LWW.3)-substitutedor unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),R^(LWW.3)-substituted or unsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, orphenyl), or R^(LWW.3)-substituted or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).In embodiments, R^(LWW.2) is independently oxo, halogen, —CX^(LWW.2) ₃,—CHX^(LWW.2) ₂, —CH₂X^(LWW.2), —OCX^(LWW.2) ₃, —OCH₂X^(LWW.2),—OCHX^(LWW.2) ₂, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H,—SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl(e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). X^(LWW.2) is independently —F, —Cl, —Br, or —I.

R^(LWW.3) is independently oxo, halogen, —CX^(LWW.3) ₃, —CHX^(LWW.3) ₂,—CH₂X^(LWW.3), —OCX^(LWW.3) ₃, —OCH₂X^(LWW.3), —OCHX^(LWW.3) ₂, —CN,—OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl(e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), or unsubstituted heteroaryl (e.g., 5to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).X^(LWW.3) is independently —F, —Cl, —Br, or —I.

In the event that any R group recited in a claim or chemical formuladescription set forth herein (R^(WW) substituent) is not specificallydefined in this disclosure, then that R group (R^(WW) group) is herebydefined as independently oxo, halogen, —CX^(WW) ₃, —CHX^(WW) ₂,—CH₂X^(WW), —OCX^(WW) ₃, —OCH₂X^(WW), —OCHX^(WW) ₂, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃,R^(WW.1)-substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), R^(WW.1)-substituted or unsubstituted heteroalkyl (e.g., 2 to8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), R^(WW.1)-substituted or unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), R^(WW.1)-substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), R^(WW.1)-substituted orunsubstituted aryl (e.g., C₆-C₁₂, C₆-C₁₀, or phenyl), orR^(WW.1)-substituted or unsubstituted heteroaryl (e.g., 5 to 12membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Again,“WW” represents the stated superscript number of the subject R group(e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). R^(WW.1), as well asX^(WW), R^(WW.2), and R^(WW.3), are as defined above.

In the event that any L linker group recited in a claim or chemicalformula description set forth herein (i.e., an L^(WW) substituent) isnot explicitly defined, then that L group (L^(WW) group) is hereindefined as independently —O—, —NH—, —COO—, —CONH—, —S—, —SO₂NH—,R^(LWW.1)-substituted or unsubstituted alkylene (e.g., C₁-C₈, C₁-C₆,C₁-C₄, or C₁-C₂), R^(LWW.1)-substituted or unsubstituted heteroalkylene(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3membered, or 4 to 5 membered), R^(LWW.1)-substituted or unsubstitutedcycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),R^(LWW.1)-substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), R^(LWW.1)-substituted or unsubstituted arylene (e.g., C₆-C₁₂,C₆-C₁₀, or phenyl), or R^(LWW.1)-substituted or unsubstitutedheteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). Again, “WW” represents the statedsuperscript number of the subject L group (e.g., 1, 2, 3, 1A, 2A, 3A,1B, 2B, 3B, etc.). R^(LWW.1) is as defined above.

For example, an R^(WW) substituent may be substituted with a firstsubstituent group R^(WW). When R^(WW) is phenyl, the said phenyl groupis optionally substituted by one or more R^(WW.1). When R^(WW.1) issubstituted alkyl (e.g., methyl), the said alkyl group is optionallysubstituted by one or more R^(WW.2). The compound that could be formedmay include, but are not limited to, the compounds depicted belowwherein R^(WW.2) is optionally substituted cyclopentyl, optionallysubstituted pyridyl, —NH₂, or optionally substituted benzoxazolyl,wherein each such optionally substituted R^(WW.2) substituent group isoptionally substituted with one or more R^(WW.3). By way of non-limitingexamples, such R^(WW.3) substituents could be independentlyunsubstituted alkyl (e.g., ethyl), halogen (e.g., fluoro), or OH, asshown below.

Certain compounds of the present disclosure possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisometricforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present disclosure. The compounds ofthe present disclosure do not include those that are known in art to betoo unstable to synthesize and/or isolate. The present disclosure ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis disclosure may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the disclosure.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of thedisclosure.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this disclosure.

The compounds of the present disclosure may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present disclosure, whether radioactive or not, areencompassed within the scope of the present disclosure.

It should be noted that throughout the application that alternatives arewritten in Markush groups, for example, each amino acid position thatcontains more than one possible amino acid. It is specificallycontemplated that each member of the Markush group should be consideredseparately, thereby comprising another embodiment, and the Markush groupis not to be read as a single unit.

“Analog,” or “analogue” is used in accordance with its plain ordinarymeaning within Chemistry and Biology and refers to a chemical compoundthat is structurally similar to another compound (i.e., a so-called“reference” compound) but differs in composition, e.g., in thereplacement of one atom by an atom of a different element, or in thepresence of a particular functional group, or the replacement of onefunctional group by another functional group, or the absolutestereochemistry of one or more chiral centers of the reference compound.Accordingly, an analog is a compound that is similar or comparable infunction and appearance but not in structure or origin to a referencecompound.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls.

Moreover, where a moiety is substituted with an R substituent, the groupmay be referred to as “R-substituted.” Where a moiety is R-substituted,the moiety is substituted with at least one R substituent and each Rsubstituent is optionally different. Where a particular R group ispresent in the description of a chemical genus (such as Formula (I)), aRoman alphabetic symbol may be used to distinguish each appearance ofthat particular R group. For example, where multiple R¹³ substituentsare present, each R¹³ substituent may be distinguished as R^(13A),R^(13B), R^(13C), R^(13D), etc., wherein each of R^(13A), R^(13B),R^(13C), R^(13D), etc. is defined within the scope of the definition ofR¹³ and optionally differently.

Descriptions of the compounds of the present disclosure are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and thelike. Also included are salts of amino acids such as arginate and thelike, and salts of organic acids like glucuronic or galactunoric acidsand the like (see, for example, Berge et al., “Pharmaceutical Salts”,Journal of Pharmaceutical Science, 1977, 66, 1-19). Certain specificcompounds of the present invention contain both basic and acidicfunctionalities that allow the compounds to be converted into eitherbase or acid addition salts.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Non-limiting examples of such salts include hydrochlorides,hydrobromides, phosphates, sulfates, methanesulfonates, nitrates,maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g.,(+)-tartrates, (−)-tartrates, or mixtures thereof including racemicmixtures), succinates, benzoates, and salts with amino acids such asglutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyliodide, and the like). These salts may be prepared by methods known tothose skilled in the art.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compound maydiffer from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Prodrugs of the compounds described herein may be convertedin vivo after administration. Additionally, prodrugs can be converted tothe compounds of the present invention by chemical or biochemicalmethods in an ex vivo environment, such as, for example, when contactedwith a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

The terms “polypeptide,” “peptide,” and “protein” are usedinterchangeably herein to refer to a polymer of amino acid residues,wherein the polymer may optionally be conjugated to a moiety that doesnot consist of amino acids. The terms apply to amino acid polymers inwhich one or more amino acid residue is an artificial chemical mimeticof a corresponding naturally occurring amino acid, as well as tonaturally occurring amino acid polymers and non-naturally occurringamino acid polymer.

A polypeptide, or a cell is “recombinant” when it is artificial orengineered, or derived from or contains an artificial or engineeredprotein or nucleic acid (e.g., non-natural or not wild type). Forexample, a polynucleotide that is inserted into a vector or any otherheterologous location, e.g., in a genome of a recombinant organism, suchthat it is not associated with nucleotide sequences that normally flankthe polynucleotide as it is found in nature is a recombinantpolynucleotide. A protein expressed in vitro or in vivo from arecombinant polynucleotide is an example of a recombinant polypeptide.Likewise, a polynucleotide sequence that does not appear in nature, forexample a variant of a naturally occurring gene, is recombinant.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.,chemical compounds including biomolecules or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated; however, the resulting reaction product can be produceddirectly from a reaction between the added reagents or from anintermediate from one or more of the added reagents that can be producedin the reaction mixture. The term “contacting” may include allowing twospecies to react, interact, or physically touch, wherein the two speciesmay be a compound as described herein and a protein or enzyme. In someembodiments contacting includes allowing a compound described herein tointeract with a protein or enzyme that is involved in a signalingpathway.

As defined herein, the term “activation”, “activate”, “activating”,“activator”, and the like in reference to a protein-inhibitorinteraction means positively affecting (e.g., increasing) the activityor function of the protein relative to the activity or function of theprotein in the absence of the activator. In embodiments activation meanspositively affecting (e.g., increasing) the concentration or levels ofthe protein relative to the concentration or level of the protein in theabsence of the activator. The terms may reference activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein decreased in a disease.Thus, activation may include, at least in part, partially or totallyincreasing stimulation, increasing or enabling activation, oractivating, sensitizing, or up-regulating signal transduction orenzymatic activity or the amount of a protein associated with a disease(e.g., a protein which is decreased in a disease relative to anon-diseased control). Activation may include, at least in part,partially or totally increasing stimulation, increasing or enablingactivation, or activating, sensitizing, or up-regulating signaltransduction or enzymatic activity or the amount of a protein.

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor interaction meansnegatively affecting (e.g., decreasing) the activity or function of theprotein relative to the activity or function of the protein in theabsence of the inhibitor. In embodiments inhibition means negativelyaffecting (e.g., decreasing) the concentration or levels of the proteinrelative to the concentration or level of the protein in the absence ofthe inhibitor. In embodiments inhibition refers to reduction of adisease or symptoms of disease. In embodiments, inhibition refers to areduction in the activity of a particular protein target. Thus,inhibition includes, at least in part, partially or totally blockingstimulation, decreasing, preventing, or delaying activation, orinactivating, desensitizing, or down-regulating signal transduction orenzymatic activity or the amount of a protein. In embodiments,inhibition refers to a reduction of activity of a target proteinresulting from a direct interaction (e.g., an inhibitor binds to thetarget protein). In embodiments, inhibition refers to a reduction ofactivity of a target protein from an indirect interaction (e.g., aninhibitor binds to a protein that activates the target protein, therebypreventing target protein activation).

The terms “inhibitor” or “repressor” or “antagonist” or “downregulator”interchangeably refer to a substance capable of detectably decreasingthe expression or activity of a given gene or protein. The antagonistcan decrease expression or activity 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90% or more in comparison to a control in the absence of theantagonist. In certain instances, expression or activity is 1.5-fold,2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression oractivity in the absence of the antagonist.

The terms “streptavidin” and

refer to a tetrameric protein (including homologs, isoforms, andfunctional fragments thereof) capable of binding biotin. The termincludes any recombinant or naturally-occurring form of streptavidinvariants thereof that maintain streptavidin activity (e.g., within atleast 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity comparedto wildtype streptavidin).

The term “expression” includes any step involved in the production ofthe polypeptide including, but not limited to, transcription,post-transcriptional modification, translation, post-translationalmodification, and secretion. Expression can be detected usingconventional techniques for detecting protein (e.g., ELISA, Westernblotting, flow cytometry, immunofluorescence, immunohistochemistry,etc.).

An “effective amount” is an amount sufficient for a compound toaccomplish a stated purpose relative to the absence of the compound(e.g., achieve the effect for which it is administered, treat a disease,reduce enzyme activity, increase enzyme activity, reduce a signalingpathway, or reduce one or more symptoms of a disease or condition). An“activity decreasing amount,” as used herein, refers to an amount ofantagonist required to decrease the activity of an enzyme relative tothe absence of the antagonist. A “function disrupting amount,” as usedherein, refers to the amount of antagonist required to disrupt thefunction of an enzyme or protein relative to the absence of theantagonist.

A “cell” as used herein, refers to a cell carrying out metabolic orother function sufficient to preserve or replicate its genomic DNA. Acell can be identified by well-known methods in the art including, forexample, presence of an intact membrane, staining by a particular dye,ability to produce progeny or, in the case of a gamete, ability tocombine with a second gamete to produce a viable offspring. Cells mayinclude prokaryotic and eukaroytic cells. Prokaryotic cells include butare not limited to bacteria. Eukaryotic cells include but are notlimited to yeast cells and cells derived from plants and animals, forexample mammalian, insect (e.g., spodoptera) and human cells. Cells maybe useful when they are naturally nonadherent or have been treated notto adhere to surfaces, for example by trypsinization.

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects. In some embodiments, acontrol is the measurement of the activity of a protein in the absenceof a compound as described herein (including embodiments and examples).

The term “modulate” is used in accordance with its plain ordinarymeaning and refers to the act of changing or varying one or moreproperties. “Modulation” refers to the process of changing or varyingone or more properties. For example, as applied to the effects of amodulator on a target protein, to modulate means to change by increasingor decreasing a property or function of the target molecule or theamount of the target molecule.

The term “aberrant” as used herein refers to different from normal. Whenused to describe enzymatic activity or protein function, aberrant refersto activity or function that is greater or less than a normal control orthe average of normal non-diseased control samples.

“Nucleic acid” or “oligonucleotide” or “polynucleotide” or grammaticalequivalents used herein means at least two nucleotides covalently linkedtogether. The term “nucleic acid” includes single-, double-, ormultiple-stranded DNA, RNA and analogs (derivatives) thereof.Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25,30, 40, 50 or more nucleotides in length, up to about 100 nucleotides inlength. Nucleic acids and polynucleotides are a polymers of any length,including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000,7000, 10,000, etc. In certain embodiments the nucleic acids hereincontain phosphodiester bonds. In other embodiments, nucleic acid analogsare included that may have alternate backbones, comprising, e.g.,phosphoramidate, phosphorothioate, phosphorodithioate, orO-methylphosphoroamidite linkages (see, Eckstein, Oligonucleotides andAnalogues: A Practical Approach, Oxford University Press); and peptidenucleic acid backbones and linkages. Other analog nucleic acids includethose with positive backbones; non-ionic backbones, and non-ribosebackbones, including those described in U.S. Pat. Nos. 5,235,033 and5,034,506, and Chapters 6 and 7, ASC Symposium Series 580, CarbohydrateModifications in Antisense Research, Sanghui & Cook, eds. Nucleic acidscontaining one or more carbocyclic sugars are also included within onedefinition of nucleic acids. Modifications of the ribose-phosphatebackbone may be done for a variety of reasons, e.g., to increase thestability and half-life of such molecules in physiological environmentsor as probes on a biochip. Mixtures of naturally occurring nucleic acidsand analogs can be made; alternatively, mixtures of different nucleicacid analogs, and mixtures of naturally occurring nucleic acids andanalogs may be made. A residue of a nucleic acid, as referred to herein,is a monomer of the nucleic acid (e.g., a nucleotide).

A particular nucleic acid sequence also encompasses “splice variants.”Similarly, a particular protein encoded by a nucleic acid encompassesany protein encoded by a splice variant of that nucleic acid. “Splicevariants,” as the name suggests, are products of alternative splicing ofa gene. After transcription, an initial nucleic acid transcript may bespliced such that different (alternate) nucleic acid splice productsencode different polypeptides. Mechanisms for the production of splicevariants vary, but include alternate splicing of exons. Alternatepolypeptides derived from the same nucleic acid by read-throughtranscription are also encompassed by this definition. Any products of asplicing reaction, including recombinant forms of the splice products,are included in this definition. An example of potassium channel splicevariants is discussed in Leicher, et al., J. Biol. Chem.273(52):35095-35101 (1998).

Nucleic acid is “operably linked” when it is placed into a functionalrelationship with another nucleic acid sequence. For example, DNA for apresequence or secretory leader is operably linked to DNA for apolypeptide if it is expressed as a preprotein that participates in thesecretion of the polypeptide; a promoter or enhancer is operably linkedto a coding sequence if it affects the transcription of the sequence; ora ribosome binding site is operably linked to a coding sequence if it ispositioned so as to facilitate translation. Generally, “operably linked”means that the DNA sequences being linked are near each other, and, inthe case of a secretory leader, contiguous and in reading phase.However, enhancers do not have to be contiguous. Linking is accomplishedby ligation at convenient restriction sites. If such sites do not exist,the synthetic oligonucleotide adaptors or linkers are used in accordancewith conventional practice.

“Nucleotide,” as used herein, refers to a nucleoside-5′-polyphosphatecompound, or a structural analog thereof, which can be incorporated(e.g., partially incorporated as a nucleoside-5′-monophosphate orderivative thereof) by a nucleic acid polymerase to extend a growingnucleic acid chain (such as a primer). Nucleotides may include basessuch as guanine (G), adenine (A), thymine, (T), uracil (U), cytosine(C), or analogues thereof, and may comprise 2, 3, 4, 5, 6, 7, 8, or morephosphates in the phosphate group. Nucleotides may be modified at one ormore of the base, sugar, or phosphate group. A nucleotide may have alabel or tag attached (a “labeled nucleotide” or “tagged nucleotide”).In embodiments, the nucleotide is a modified nucleotide which terminatesprimer extension reversibly. In embodiments, nucleotides may furtherinclude a polymerase-compatible cleavable moiety covalently bound to the3′ oxygen.

A “nucleoside” is structurally similar to a nucleotide but lacks thephosphate moieties. An example of a nucleoside analog would be one inwhich the label is linked to the base and there is no phosphate groupattached to the sugar molecule.

The terms also encompass nucleic acids containing known nucleotideanalogs or modified backbone residues or linkages, which are synthetic,naturally occurring, or non-naturally occurring, which have similarbinding properties as the reference nucleic acid, and which aremetabolized in a manner similar to the reference nucleotides. Examplesof such analogs include, without limitation, phosphodiester derivativesincluding, e.g., phosphoramidate, phosphorodiamidate, phosphorothioate(also known as phosphothioate having double bonded sulfur replacingoxygen in the phosphate), phosphorodithioate, phosphonocarboxylic acids,phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid,methyl phosphonate, boron phosphonate, or O-methylphosphoroamiditelinkages (see, Eckstein, Oligonucleotides and Analogues: A PracticalApproach, Oxford University Press) as well as modifications to thenucleotide bases such as in 5-methyl cytidine or pseudouridine; andpeptide nucleic acid backbones and linkages. Other analog nucleic acidsinclude those with positive backbones; non-ionic backbones, modifiedsugars, and non-ribose backbones (e.g., phosphorodiamidate morpholinooligos or locked nucleic acids (LNA) as known in the art), includingthose described in U.S. Pat. Nos. 5,235,033 and 5,034,506, and Chapters6 and 7, ASC Symposium Series 580, Carbohydrate Modifications inAntisense Research, Sanghui & Cook, eds. Nucleic acids containing one ormore carbocyclic sugars are also included within one definition ofnucleic acids. Modifications of the ribose-phosphate backbone may bedone for a variety of reasons, e.g., to increase the stability andhalf-life of such molecules in physiological environments or as probeson a biochip. Mixtures of naturally occurring nucleic acids and analogscan be made; alternatively, mixtures of different nucleic acid analogs,and mixtures of naturally occurring nucleic acids and analogs may bemade. In embodiments, the internucleotide linkages in DNA arephosphodiester, phosphodiester derivatives, or a combination of both.

In embodiments, “nucleotide analogue,” “nucleotide analog,” or“nucleotide derivative” shall mean an analogue of A, G, C, T or U (thatis, an analogue or derivative of a nucleotide comprising the base A, G,C, T or U), including a phosphate group, which may be recognized by DNAor RNA polymerase (whichever is applicable) and may be incorporated intoa strand of DNA or RNA (whichever is appropriate). Examples ofnucleotide analogues include, without limitation, 7-deaza-adenine,7-deaza-guanine, the analogues of deoxynucleotides shown herein,analogues in which a label is attached through a cleavable linker to the5-position of cytosine or thymine or to the 7-position of deaza-adenineor deaza-guanine, and analogues in which a small chemical moiety is usedto cap the —OH group at the 3-position of deoxyribose. Nucleotideanalogues and DNA polymerase-based DNA sequencing are also described inU.S. Pat. No. 6,664,079, which is incorporated herein by reference inits entirety for all purposes.

The terms “identical” or percent “identity,” in the context of two ormore nucleic acids or polypeptide sequences, refer to two or moresequences or subsequences that are the same or have a specifiedpercentage of amino acid residues or nucleotides that are the same(i.e., about 60% identity, preferably 61%, 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% or higher identity over a specified region whencompared and aligned for maximum correspondence over a comparison windowor designated region) as measured using a BLAST or BLAST 2.0 sequencecomparison algorithms with default parameters described below, or bymanual alignment and visual inspection (see, e.g., NCBI web site or thelike). Such sequences are then said to be “substantially identical.”This definition also refers to, or may be applied to, the compliment ofa test sequence. The definition also includes sequences that havedeletions and/or additions, as well as those that have substitutions. Asdescribed below, the preferred algorithms can account for gaps and thelike. Preferably, identity exists over a region that is at least about10 amino acids or 20 nucleotides in length, or more preferably over aregion that is 10-50 amino acids or 20-50 nucleotides in length. As usedherein, percent (%) amino acid sequence identity is defined as thepercentage of amino acids in a candidate sequence that are identical tothe amino acids in a reference sequence, after aligning the sequencesand introducing gaps, if necessary, to achieve the maximum percentsequence identity. Alignment for purposes of determining percentsequence identity can be achieved in various ways that are within theskill in the art, for instance, using publicly available computersoftware such as BLAST, BLAST-2, ALIGN, ALIGN-2, or Megalign (DNASTAR)software. Appropriate parameters for measuring alignment, including anyalgorithms needed to achieve maximal alignment over the full-length ofthe sequences being compared can be determined by known methods.

For sequence comparisons, typically one sequence acts as a referencesequence, to which test sequences are compared. When using a sequencecomparison algorithm, test and reference sequences are entered into acomputer, subsequence coordinates are designated, if necessary, andsequence algorithm program parameters are designated. Preferably,default program parameters can be used, or alternative parameters can bedesignated. The sequence comparison algorithm then calculates thepercent sequence identities for the test sequences relative to thereference sequence, based on the program parameters.

A “comparison window”, as used herein, includes reference to a segmentof any one of the number of contiguous positions selected from the groupconsisting of from 10 to 600, usually about 50 to about 200, moreusually about 100 to about 150 in which a sequence may be compared to areference sequence of the same number of contiguous positions after thetwo sequences are optimally aligned. Methods of alignment of sequencesfor comparison are well-known in the art. Optimal alignment of sequencesfor comparison can be conducted, e.g., by the local homology algorithmof Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homologyalignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970),by the search for similarity method of Pearson & Lipman, Proc. Nat'l.Acad. Sci. USA 85:2444 (1988), by computerized implementations of thesealgorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin GeneticsSoftware Package, Genetics Computer Group, 575 Science Dr., Madison,WI), or by manual alignment and visual inspection (see, e.g., CurrentProtocols in Molecular Biology (Ausubel et al., eds. 1995 supplement)).

The term “bioconjugate group” or “bioconjugate reactive moiety” or“bioconjugate reactive group” refers to a chemical moiety whichparticipates in a reaction to form bioconjugate linker (e.g., covalentlinker). Non-limiting examples of bioconjugate groups include —NH₂,—COOH, —COOCH₃, —N-hydroxysuccinimide, -maleimide,

In embodiments, the bioconjugate reactive group may be protected (e.g.,with a protecting group). In embodiments, the bioconjugate reactivemoiety is

or —NH₂.

As used herein, the term “bioconjugate” or “bioconjugate linker” refersto the resulting association between atoms or molecules of bioconjugatereactive groups. The association can be direct or indirect. For example,a conjugate between a first bioconjugate reactive group (e.g., —NH₂,—COOH, —N-hydroxysuccinimide, or -maleimide) and a second bioconjugatereactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine,amine sidechain containing amino acid, or carboxylate) provided hereincan be direct, e.g., by covalent bond or linker (e.g., a first linker ofsecond linker), or indirect, e.g., by non-covalent bond (e.g.,electrostatic interactions (e.g., ionic bond, hydrogen bond, halogenbond), van der Waals interactions (e.g., dipole-dipole, dipole-induceddipole, London dispersion), ring stacking (pi effects), hydrophobicinteractions and the like). In embodiments, bioconjugates orbioconjugate linkers are formed using bioconjugate chemistry (i.e., theassociation of two bioconjugate reactive groups) including, but are notlimited to nucleophilic substitutions (e.g., reactions of amines andalcohols with acyl halides, active esters), electrophilic substitutions(e.g., enamine reactions) and additions to carbon-carbon andcarbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alderaddition). These and other useful reactions are discussed in, forexample, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons,New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, SanDiego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances inChemistry Series, Vol. 198, American Chemical Society, Washington, D.C.,1982. In embodiments, the first bioconjugate reactive group (e.g.,maleimide moiety) is covalently attached to the second bioconjugatereactive group (e.g., a sulfhydryl). In embodiments, the firstbioconjugate reactive group (e.g., haloacetyl moiety) is covalentlyattached to the second bioconjugate reactive group (e.g., a sulfhydryl).In embodiments, the first bioconjugate reactive group (e.g., pyridylmoiety) is covalently attached to the second bioconjugate reactive group(e.g., a sulfhydryl). In embodiments, the first bioconjugate reactivegroup (e.g., —N-hydroxysuccinimide moiety) is covalently attached to thesecond bioconjugate reactive group (e.g., an amine). In embodiments, thefirst bioconjugate reactive group (e.g., maleimide moiety) is covalentlyattached to the second bioconjugate reactive group (e.g., a sulfhydryl).In embodiments, the first bioconjugate reactive group (e.g.,-sulfo-N-hydroxysuccinimide moiety) is covalently attached to the secondbioconjugate reactive group (e.g., an amine). In embodiments, the firstbioconjugate reactive group (e.g., —COOH) is covalently attached to thesecond bioconjugate reactive group

thereby forming a bioconjugate

In embodiments, the first bioconjugate reactive group (e.g., —NH₂) iscovalently attached to the second bioconjugate reactive group

thereby forming a bioconjugate

In embodiments, the first bioconjugate reactive group (e.g., a couplingreagent) is covalently attached to the second bioconjugate reactivegroup

thereby forming a bioconjugate

Useful bioconjugate reactive moieties used for bioconjugate chemistriesherein include, for example:

-   -   (a) carboxyl groups and various derivatives thereof including,        but not limited to, N-hydroxysuccinimide esters,        N-hydroxybenztriazole esters, acid halides, acyl imidazoles,        thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and        aromatic esters;    -   (b) hydroxyl groups which can be converted to esters, ethers,        aldehydes, etc.    -   (c) haloalkyl groups wherein the halide can be later displaced        with a nucleophilic group such as, for example, an amine, a        carboxylate anion, thiol anion, carbanion, or an alkoxide ion,        thereby resulting in the covalent attachment of a new group at        the site of the halogen atom;    -   (d) dienophile groups which are capable of participating in        Diels-Alder reactions such as, for example, maleimido or        maleimide groups;    -   (e) aldehyde or ketone groups such that subsequent        derivatization is possible via formation of carbonyl derivatives        such as, for example, imines, hydrazones, semicarbazones or        oximes, or via such mechanisms as Grignard addition or        alkyllithium addition;    -   (f) sulfonyl halide groups for subsequent reaction with amines,        for example, to form sulfonamides;    -   (g) thiol groups, which can be converted to disulfides, reacted        with acyl halides, or bonded to metals such as gold, or react        with maleimides;    -   (h) amine or sulfhydryl groups (e.g., present in cysteine),        which can be, for example, acylated, alkylated or oxidized;    -   (i) alkenes, which can undergo, for example, cycloadditions,        acylation, Michael addition, etc;    -   (j) epoxides, which can react with, for example, amines and        hydroxyl compounds;    -   (k) phosphoramidites and other standard functional groups useful        in nucleic acid synthesis;    -   (l) metal silicon oxide bonding;    -   (m) metal bonding to reactive phosphorus groups (e.g.,        phosphines) to form, for example, phosphate diester bonds;    -   (n) azides coupled to alkynes using copper catalyzed        cycloaddition click chemistry; and    -   (o) biotin conjugate can react with avidin or strepavidin to        form a avidin-biotin complex or streptavidin-biotin complex.

The bioconjugate reactive groups can be chosen such that they do notparticipate in, or interfere with, the chemical stability of theconjugate described herein. Alternatively, a reactive functional groupcan be protected from participating in the crosslinking reaction by thepresence of a protecting group. In embodiments, the bioconjugatecomprises a molecular entity derived from the reaction of an unsaturatedbond, such as a maleimide, and a sulfhydryl group.

The term “monophosphate” is used in accordance with its ordinary meaningin the arts and refers to a moiety having the formula:

The term “polyphosphate” refers to at least two phosphate groups, havingthe formula:

wherein np is an integer of 1 or greater. In embodiments, np is aninteger from 0 to 5. In embodiments, np is an integer from 0 to 2. Inembodiments, np is 2.

The term “base” as used herein refers to a divalent purine or pyrimidinecompound or a derivative thereof, that may be a constituent of nucleicacid (i.e., DNA or RNA, or a derivative thereof). In embodiments, thebase is a derivative of a naturally occurring DNA or RNA base (e.g., abase analogue). In embodiments, the base is a hybridizing base. Inembodiments, the base hybridizes to a complementary base. Inembodiments, the base is capable of forming at least one hydrogen bondwith a complementary base (e.g., adenine hydrogen bonds with thymine,adenine hydrogen bonds with uracil, guanine pairs with cytosine).Non-limiting examples of a base include divalent forms of cytosine or aderivative thereof (e.g., cytosine analogue), guanine or a derivativethereof (e.g., guanine analogue), adenine or a derivative thereof (e.g.,adenine analogue), thymine or a derivative thereof (e.g., thymineanalogue), uracil or a derivative thereof (e.g., uracil analogue),hypoxanthine or a derivative thereof (e.g., hypoxanthine analogue),xanthine or a derivative thereof (e.g., xanthine analogue),7-methylguanine or a derivative thereof (e.g., 7-methylguanineanalogue), deaza-adenine or a derivative thereof (e.g., deaza-adenineanalogue), deaza-guanine or a derivative thereof (e.g., deaza-guanine),deaza-hypoxanthine or a derivative thereof, 5,6-dihydrouracil or aderivative thereof (e.g., 5,6-dihydrouracil analogue), 5-methylcytosineor a derivative thereof (e.g., 5-methylcytosine analogue), or5-hydroxymethylcytosine or a derivative thereof (e.g.,5-hydroxymethylcytosine analogue). In embodiments, the base is adivalent form of adenine, guanine, hypoxanthine, xanthine, theobromine,caffeine, uric acid, or isoguanine. In embodiments, the base is

The term “non-covalent linker” is used in accordance with its ordinarymeaning and refers to a divalent moiety which includes at least twomolecules that are not covalently linked to each other but are capableof interacting with each other via a non-covalent bond (e.g.,electrostatic interactions (e.g., ionic bond, hydrogen bond, halogenbond) or van der Waals interactions (e.g., dipole-dipole, dipole-induceddipole, London dispersion). In embodiments, the non-covalent linker isthe result of two molecules that are not covalently linked to each otherthat interact with each other via a non-covalent bond.

The term “cleavable linker” or “cleavable moiety” as used herein refersto a divalent or monovalent, respectively, moiety which is capable ofbeing separated (e.g., detached, split, disconnected, hydrolyzed, astable bond within the moiety is broken) into distinct entities. Acleavable linker is cleavable (e.g., specifically cleavable) in responseto external stimuli (e.g., enzymes, nucleophilic/basic reagents,reducing agents, photo-irradiation, electrophilic/acidic reagents,organometallic and metal reagents, or oxidizing reagents). A chemicallycleavable linker refers to a linker which is capable of being split inresponse to the presence of a chemical (e.g., acid, base, oxidizingagent, reducing agent, Pd(0), tris-(2-carboxyethyl)phosphine, dilutenitrous acid, fluoride, tris(3-hydroxypropyl)phosphine), sodiumdithionite (Na₂S₂O₄), or hydrazine (N₂H₄)). A chemically cleavablelinker is non-enzymatically cleavable. In embodiments, the cleavablelinker is cleaved by contacting the cleavable linker with a cleavingagent. In embodiments, the cleaving agent is a phosphine containingreagent (e.g., TCEP or THPP), sodium dithionite (Na₂S₂O₄), weak acid,hydrazine (N₂H₄), Pd(0), or light-irradiation (e.g., ultravioletradiation).

A photocleavable linker (e.g., including or consisting of ano-nitrobenzyl group) refers to a linker which is capable of being splitin response to photo-irradiation (e.g., ultraviolet radiation). Anacid-cleavable linker refers to a linker which is capable of being splitin response to a change in the pH (e.g., increased acidity). Abase-cleavable linker refers to a linker which is capable of being splitin response to a change in the pH (e.g., decreased acidity). Anoxidant-cleavable linker refers to a linker which is capable of beingsplit in response to the presence of an oxidizing agent. Areductant-cleavable linker refers to a linker which is capable of beingsplit in response to the presence of an reducing agent (e.g.,Tris(3-hydroxypropyl)phosphine). In embodiments, the cleavable linker isa dialkylketal linker, an azo linker, an allyl linker, a cyanoethyllinker, a 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)ethyl linker, or anitrobenzyl linker.

The term “orthogonally cleavable linker” or “orthogonal cleavablelinker” as used herein refer to a cleavable linker that is cleaved by afirst cleaving agent (e.g., enzyme, nucleophilic/basic reagent, reducingagent, photo-irradiation, electrophilic/acidic reagent, organometallicand metal reagent, oxidizing reagent) in a mixture of two or moredifferent cleaving agents and is not cleaved by any other differentcleaving agent in the mixture of two or more cleaving agents. Forexample, two different cleavable linkers are both orthogonal cleavablelinkers when a mixture of the two different cleavable linkers arereacted with two different cleaving agents and each cleavable linker iscleaved by only one of the cleaving agents and not the other cleavingagent. In embodiments, an orthogonally cleavable linker is a cleavablelinker that, following cleavage (e.g., following exposure to a cleavingagent), the two separated entities (e.g., fluorescent dye, bioconjugatereactive group) do not further react and form a new orthogonallycleavable linker.

The term “polymer” refers to a molecule including repeating subunits(e.g., polymerized monomers). For example, polymeric molecules may bebased upon polyethylene glycol (PEG), tetraethylene glycol (TEG),polyvinylpyrrolidone (PVP), poly(xylene), or poly(p-xylylene). The term“polymerizable monomer” is used in accordance with its meaning in theart of polymer chemistry and refers to a compound that may covalentlybind chemically to other monomer molecules (such as other polymerizablemonomers that are the same or different) to form a polymer. Inembodiments, polymer refers to PEG, having the formula:

wherein n1 is an integer from 1 to 30.

The term “coupling reagent” is used in accordance with its plainordinary meaning in the arts and refers to a substance (e.g., a compoundor solution) which participates in chemical reaction and results in theformation of a covalent bond (e.g., between bioconjugate reactivemoieties, between a bioconjugate reactive moiety and the couplingreagent). In embodiments, the level of reagent is depleted in the courseof a chemical reaction. This is in contrast to a solvent, whichtypically does not get consumed over the course of the chemicalreaction. In embodiments, the coupling reagent is a phosphonium reagent.Non-limiting examples of coupling reagents includedicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC),(N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide (EDAC),(1-Hydroxybenzotriazole) (HOBt),(Hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine) (HOOBt),(4-(N,N-Dimethylamino)pyridine) (DMAP),(Benzotriazol-1-yloxy-tris(dimethylamino)-phosphoniumhexafluorophosphate) (BOP), (Bromo-tripyrrolidino-phosphoniumhexafluorophosphate) (PyBrOP), (Ethylcyano(hydroxyimino)acetato-O2)-tri-(1-pyrrolidinyl)-phosphoniumhexafluorophosphate) (PyOxim),(3-(Diethoxy-phosphoryloxy)-1,2,3-benzo[d] triazin-4(3H)-one) (DEPBT),(2-(1H-Benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumtetrafluoroborate/hexafluorophosphate) (TBTU),(2-(6-Chloro-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumhexafluorophosphate) (HCTU),(N-[(5-Chloro-1H-benzotriazol-1-yl)-dimethylamino-morpholino]-uroniumhexafluorophosphate N-oxide) (HDMC),(2-(7-Aza-1H-benzotriazol-1-yl)-N,N,N′,N′-tetramethylaminiumtetrafluoroborate/hexafluorophosphate) (TATU),(2-(1-Oxy-pyridin-2-yl)-1,1,3,3-tetramethylisothiouroniumtetrafluoroborate) (TOTT), (Tetramethylfluoroformamidiniumhexafluorophosphate) (TFFH),benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP), 7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyAOP),6-Chloro-benzotriazole-1-yloxy-tris-pyrrolidinophosphoniumhexafluorophosphate (PyClock),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU), or2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU).

The term “solution” is used in accordance with its plain ordinarymeaning in the arts and refers to a liquid mixture in which the minorcomponent (e.g., a solute or compound) is distributed (e.g., uniformlydistributed) within the major component (e.g., a solvent).

The term “organic solvent” as used herein is used in accordance with itsordinary meaning in chemistry and refers to a solvent which includescarbon. Non-limiting examples of organic solvents include acetic acid,acetone, acetonitrile, benzene, 1-butanol, 2-butanol, 2-butanone,t-butyl alcohol, carbon tetrachloride, chlorobenzene, chloroform,cyclohexane, 1,2-dichloroethane, diethylene glycol, diethyl ether,diglyme (diethylene glycol, dimethyl ether), 1,2-dimethoxyethane (glyme,DME), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,4-dioxane,ethanol, ethyl acetate, ethylene glycol, glycerin, heptane,hexamethylphosphoramide (HMPA), hexamethylphosphorous, triamide (HMPT),hexane, methanol, methyl t-butyl ether (MTBE), methylene chloride,N-methyl-2-pyrrolidinone (NMP), nitromethane, pentane, petroleum ether(ligroine), 1-propanol, 2-propanol, pyridine, tetrahydrofuran (THF),toluene, triethyl amine, o-xylene, m-xylene, or p-xylene. Inembodiments, the organic solvent is or includes chloroform,dichloromethane, methanol, ethanol, tetrahydrofuran, or dioxane.

As used herein, the term “salt” refers to acid or base salts of thecompounds described herein. Illustrative examples of acceptable saltsare mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid,and the like) salts, organic acid (acetic acid, propionic acid, glutamicacid, citric acid and the like) salts, quaternary ammonium (methyliodide, ethyl iodide, and the like) salts. In embodiments, compounds maybe presented with a positive charge, for example

and it is understood an appropriate counter-ion (e.g., chloride ion,fluoride ion, or acetate ion) may also be present, though not explicitlyshown. Likewise, for compounds having a negative charge

it is understood an appropriate counter-ion (e.g., a proton, sodium ion,potassium ion, or ammonium ion) may also be present, though notexplicitly shown. The protonation state of the compound (e.g., acompound described herein) depends on the local environment (i.e., thepH of the environment), therefore, in embodiments, the compound may bedescribed as having a moiety in a protonated state

or an ionic state

and it is understood these are interchangable. In embodiments, thecounter-ion is represented by the symbol M (e.g., M⁺ or M⁻).

As used herein, the term “about” means a range of values including thespecified value, which a person of ordinary skill in the art wouldconsider reasonably similar to the specified value. In embodiments,about means within a standard deviation using measurements generallyacceptable in the art. In embodiments, about means a range extending to+/−10% of the specified value. In embodiments, about includes thespecified value.

The term “protecting group” is used in accordance with its ordinarymeaning in organic chemistry and refers to a moiety covalently bound toa heteroatom, heterocycloalkyl, or heteroaryl to prevent reactivity ofthe heteroatom, heterocycloalkyl, or heteroaryl during one or morechemical reactions performed prior to removal of the protecting group.Typically a protecting group is bound to a heteroatom (e.g., O) during apart of a multipart synthesis wherein it is not desired to have theheteroatom react (e.g., a chemical reduction) with the reagent.Following protection the protecting group may be removed (e.g., bymodulating the pH). In embodiments the protecting group is an alcoholprotecting group. Non-limiting examples of alcohol protecting groupsinclude acetyl, benzoyl, benzyl, methoxymethyl ether (MOM),tetrahydropyranyl (THP), and silyl ether (e.g., trimethylsilyl (TMS)).In embodiments the protecting group is an amine protecting group.Non-limiting examples of amine protecting groups include carbobenzyloxy(Cbz), tert-butyloxycarbonyl (BOC), 9-Fluorenylmethyloxycarbonyl (FMOC),acetyl, benzoyl, benzyl, carbamate, p-methoxybenzyl ether (PMB), andtosyl (Ts).

The term “polymerase-compatible cleavable moiety” or a “reversibleterminator moiety” as used herein refers to a cleavable moiety whichdoes not interfere with the function of a polymerase (e.g., DNApolymerase, modified DNA polymerase). Methods for determining thefunction of a polymerase contemplated herein are described in B.Rosenblum et al. (Nucleic Acids Res. 1997 Nov. 15; 25(22): 4500-4504);and Z. Zhu et al. (Nucleic Acids Res. 1994 Aug. 25; 22(16): 3418-3422),which are incorporated by reference herein in their entirety for allpurposes. In embodiments, the polymerase-compatible cleavable moietydoes not decrease the function of a polymerase relative to the absenceof the polymerase-compatible cleavable moiety. In embodiments, thepolymerase-compatible cleavable moiety does not negatively affect DNApolymerase recognition. In embodiments, the polymerase-compatiblecleavable moiety does not negatively affect (e.g., limit) the readlength of the DNA polymerase. Additional examples of apolymerase-compatible cleavable moiety may be found in U.S. Pat. No.6,664,079, Ju J. et al. (2006) Proc Natl Acad Sci USA103(52):19635-19640; Ruparel H. et al. (2005) Proc Natl Acad Sci USA102(17):5932-5937; Wu J. et al. (2007) Proc Natl Acad Sci USA104(104):16462-16467; Guo J. et al. (2008) Proc Natl Acad Sci USA105(27): 9145-9150 Bentley D. R. et al. (2008) Nature 456(7218):53-59;or Hutter D. et al. (2010) Nucleosides Nucleotides & Nucleic Acids29:879-895, which are incorporated herein by reference in their entiretyfor all purposes. In embodiments, a polymerase-compatible cleavablemoiety includes an azido moiety or a dithiol linking moiety. Inembodiments, the polymerase-compatible cleavable moiety is independently—NH₂, —CN, —CH₃, C₂-C₆ allyl (e.g., —CH₂—CH═CH₂), methoxyalkyl (e.g.,—CH₂—O—CH₃), or —CH₂N₃. In embodiments, the polymerase-compatiblecleavable moiety comprises a disulfide moiety. In embodiments, apolymerase-compatible cleavable moiety is a cleavable moiety on anucleotide, nucleobase, nucleoside, or nucleic acid that does notinterfere with the function of a polymerase (e.g., DNA polymerase,modified DNA polymerase). In embodiments, the reversible terminatormoiety is

The term “allyl” as described herein refers to an unsubstitutedmethylene attached to a vinyl group (i.e., —CH═CH₂), having the formula

An “allyl linker” refers to a divalent unsubstituted methylene attachedto a vinyl group, having the formula

The terms “DNA polymerase” and “nucleic acid polymerase” are used inaccordance with their plain ordinary meaning and refer to enzymescapable of synthesizing nucleic acid molecules from nucleotides (e.g.,deoxyribonucleotides). Typically, a DNA polymerase adds nucleotides tothe 3′-end of a DNA strand, one nucleotide at a time. In embodiments,the DNA polymerase is a Pol I DNA polymerase, Pol II DNA polymerase, PolIII DNA polymerase, Pol IV DNA polymerase, Pol V DNA polymerase, Pol βDNA polymerase, Pol μ DNA polymerase, Pol λ DNA polymerase, Pol σ DNApolymerase, Pol α DNA polymerase, Pol δ DNA polymerase, Pol ε DNApolymerase, Pol η DNA polymerase, Pol ι DNA polymerase, Pol κ DNApolymerase, Pol ζ DNA polymerase, Pol γ DNA polymerase, Pol θ DNApolymerase, Pol υ DNA polymerase, or a thermophilic nucleic acidpolymerase (e.g., Taq polymerase, Therminator γ, 9°N polymerase (exo-),Therminator II, Therminator III, or Therminator IX).

A person of ordinary skill in the art will understand when a variable(e.g., moiety or linker) of a compound or of a compound genus (e.g., agenus described herein) is described by a name or formula of astandalone compound with all valencies filled, the unfilled valence(s)of the variable will be dictated by the context in which the variable isused. For example, when a variable of a compound as described herein isconnected (e.g., bonded) to the remainder of the compound through asingle bond, that variable is understood to represent a monovalent form(i.e., capable of forming a single bond due to an unfilled valence) of astandalone compound (e.g., if the variable is named “methane” in anembodiment but the variable is known to be attached by a single bond tothe remainder of the compound, a person of ordinary skill in the artwould understand that the variable is actually a monovalent form ofmethane, i.e., methyl or —CH₃). Likewise, for a linker variable (e.g.,L¹, L², L³, or L⁴ as described herein), a person of ordinary skill inthe art will understand that the variable is the divalent form of astandalone compound (e.g., if the variable is assigned to “PEG” or“polyethylene glycol” in an embodiment but the variable is connected bytwo separate bonds to the remainder of the compound, a person ofordinary skill in the art would understand that the variable is adivalent (i.e., capable of forming two bonds through two unfilledvalences) form of PEG instead of the standalone compound PEG).

The term “leaving group” is used in accordance with its ordinary meaningin chemistry and refers to a moiety (e.g., atom, functional group, ormolecule) that separates from the molecule following a chemical reaction(e.g., bond formation, reductive elimination, condensation, orcross-coupling reaction) involving an atom or chemical moiety to whichthe leaving group is attached, also referred to herein as the “leavinggroup reactive moiety”, and a complementary reactive moiety (i.e., achemical moiety that reacts with the leaving group reactive moiety) toform a new bond between the remnants of the leaving groups reactivemoiety and the complementary reactive moiety. Thus, the leaving groupreactive moiety and the complementary reactive moiety form acomplementary reactive group pair. Non limiting examples of leavinggroups include hydrogen, hydroxide, halogen (e.g., Br),perfluoroalkylsulfonates (e.g., triflate), tosylates, mesylates, water,alcohols, nitrate, phosphate, thioether, amines, ammonia, fluoride,carboxylate, phenoxides, boronic acid, boronate esters, substituted orunsubstituted piperazinyl, and alkoxides. In embodiments, two moleculesare allowed to contact, wherein at least one of the molecules has aleaving group, and upon a reaction and/or bond formation (e.g., acyloincondensation, aldol condensation, Claisen condensation, or Stillereaction) the leaving group(s) separate from the respective molecule. Inembodiments, a leaving group is a bioconjugate reactive moiety. Inembodiments, the leaving groups is designed to facilitate the reaction.In embodiments, the leaving group is a substituent group.

The terms “detect” and “detecting” as used herein refer to the act ofviewing (e.g., imaging, indicating the presence of, quantifying, ormeasuring (e.g., spectroscopic measurement), an agent based on anidentifiable characteristic of the agent, for example, the light emittedfrom the present compounds. For example, the compound described hereincan be bound to an agent, and, upon being exposed to an absorptionlight, will emit an emission light. The presence of an emission lightcan indicate the presence of the agent. Likewise, the quantification ofthe emitted light intensity can be used to measure the concentration ofthe agent.

As used herein, the term “kit” refers to any delivery system fordelivering materials. In the context of reaction assays, such deliverysystems include systems that allow for the storage, transport, ordelivery of reaction reagents (e.g., oligonucleotides, enzymes, etc. inthe appropriate containers) and/or supporting materials (e.g., buffers,written instructions for performing the assay, etc.) from one locationto another. For example, kits include one or more enclosures (e.g.,boxes) containing the relevant reaction reagents and/or supportingmaterials. As used herein, the term “fragmented kit” refers to adelivery system comprising two or more separate containers that eachcontain a subportion of the total kit components. The containers may bedelivered to the intended recipient together or separately. For example,a first container may contain an enzyme for use in an assay, while asecond container contains oligonucleotides. In contrast, a “combinedkit” refers to a delivery system containing all of the components of areaction assay in a single container (e.g., in a single box housing eachof the desired components). The term “kit” includes both fragmented andcombined kits.

The terms “fluorophore” or “fluorescent agent” are used interchangeablyand refer to a substance, compound, agent, or composition (e.g.,compound) that can absorb light at one or more wavelengths and re-emitlight at one or more longer wavelengths, relative to the one or morewavelengths of absorbed light. Examples of fluorophores that may beincluded in the compounds and compositions described herein includefluorescent proteins, xanthene derivatives (e.g., fluorescein,rhodamine, Oregon green, eosin, or Texas red), cyanine and derivatives(e.g., cyanine, indocarbocyanine, oxacarbocyanine, thiacarbocyanine, ormerocyanine), napththalene derivatives (e.g., dansyl or prodanderivatives), coumarin and derivatives, oxadiazole derivatives (e.g.,pyridyloxazole, nitrobenzoxadiazole or benzoxadiazole), anthracenederivatives (e.g., anthraquinones, DRAQ5, DRAQ7, or CyTRAK Orange),pyrene derivatives (e.g., cascade blue and derivatives), oxazinederivatives (e.g., Nile red, Nile blue, cresyl violet, or oxazine 170),acridine derivatives (e.g., proflavin, acridine orange, acridineyellow), arylmethine derivatives (e.g., auramine, crystal violet, ormalachite green), tetrapyrrole derivatives (e.g., porphin,phthalocyanine, bilirubin), CF Dye™, DRAQ™, CyTRAK™, BODIPY™, AlexaFluor™ DyLight Fluor™, Atto™, Tracy™, FluoProbes™, Abberior Dyes™, DY™dyes, MegaStokes Dyes™, Sulfo Cy™, Seta™ dyes, SeTau™ dyes, SquareDyes™, Quasar™ dyes, Cal Fluor™ dyes, SureLight Dyes™, PerCP™,Phycobilisomes™, APC™, APCXL™, RPE™ and/or BPE™. A fluorescent moiety isa radical of a fluorescent agent. The emission from the fluorophores canbe detected by any number of methods, including but not limited to,fluorescence spectroscopy, fluorescence microscopy, fluorimeters,fluorescent plate readers, infrared scanner analysis, laser scanningconfocal microscopy, automated confocal nanoscanning, laserspectrophotometers, fluorescent-activated cell sorters (FACS),image-based analyzers and fluorescent scanners (e.g., gel/membranescanners).

II. Compounds and Kits

In an aspect is provided a compound, or salt thereof, having theformula:

L³ is a bond, —S(O)₂—, —NH—, —O—, —S—, —C(O)—, —C(O)NR¹—, —NR¹C(O)—,—NR¹C(O)NR^(1A)—, —S(O)₂NR¹—, —NR¹S(O)₂—, substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, L³ does notinclude a —C(O)O— moiety. In embodiments, L³ is not —C(O)O—. Inembodiments, L³ does not include an —OC(O)— moiety. In embodiments, L³is not —OC(O)—. In embodiments, L³ is not —C(O)NH—.

L¹ and L² are each independently a bond or a covalent linker. Inembodiments, at least one of L¹, L², and L³ is not a bond. Inembodiments, L³ is not a bond. In embodiments, L² is not a bond. Inembodiments, L¹ is not a bond.

R¹, R^(1A), R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, halogen,—CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl,—CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂,—OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl.

R² and R³ are each independently substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl.

R⁸ is hydrogen, a bioconjugate reactive moiety, a nucleotide, anucleoside, or a nucleic acid.

R⁹, R¹⁰, R¹¹, and R¹² are each independently hydrogen, substituted orunsubstituted alkyl, or substituted or unsubstituted heteroalkyl.

R⁴ and R⁵ substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted heteroaryl.

R⁶ and R⁷ substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted heteroaryl.

R⁴ and R⁹ substituents may optionally be joined to form a substituted orunsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl.

R⁷ and R¹⁰ substituents may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl.

R⁵ and R¹¹ substituents may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl.

R⁶ and R¹² substituents may optionally be joined to form a substitutedor unsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl.

In embodiments, R¹, R^(1A), R⁴, R⁵, R⁶, and R⁷ are each independentlyhydrogen, halogen, —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂,—CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂, —COOH, —CONH₂, —SH,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

In embodiments, R¹ is independently halogen, —CF₃, —CCl₃, —CI₃, —CBr₃,—CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F,—OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃,—OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)OH, —NHOH, —N₃, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R¹ is not hydrogen.

In embodiments, R¹ is independently halogen, —CF₃, —CBr₃, —CCl₃, —CI₃,—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂,—COOH, —CONH₂, —SH, substituted or unsubstituted alkyl, substituted orunsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocycloalkyl, substituted orunsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R^(1A) is independently halogen, —CF₃, —CCl₃, —CI₃,—CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, R^(1A) is not hydrogen.

In embodiments, R^(1A) is independently halogen, —CF₃, —CBr₃, —CCl₃,—CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH,—NH₂, —COOH, —CONH₂, —SH, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl.

In embodiments, R⁸ is hydrogen, a bioconjugate reactive moiety, or anucleic acid. In embodiments, R⁸ is hydrogen or a bioconjugate reactivemoiety. In embodiments, R⁸ is a nucleotide or nucleoside. Inembodiments, R⁸ is a nucleotide. In embodiments, R⁸ is a nucleoside. Inembodiments, R⁸ is a nucleic acid.

In embodiments, the compound, or salt thereof, has the formula:

L¹, L², R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are asdescribed herein.

In an aspect is provided a compound, or salt thereof, having theformula:

L¹, L², L³, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, and R¹² are asdescribed herein. L⁴ is a bond, —S(O)₂—, —NH—, —O—, —S—, —C(O)—,—C(O)NR⁵⁴—, —NR⁵⁴C(O)—, —NR⁵⁴C(O)NR^(54A)—, —S(O)₂NR⁵⁴—, —NR⁵⁴S(O)₂—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene. R⁵⁴ and R^(54A)are each independently hydrogen, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃,—CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F,—OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃,—OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). R¹⁴ is independently hydrogen, halogen,—CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl,—CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂,—OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH,—CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃,substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl),substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered), or a polymer (e.g., a monovalentpolymer). In embodiments, L⁴ does not include a —C(O)O— moiety. Inembodiments, L⁴ is not —C(O)O—. In embodiments, L⁴ does not include an—OC(O)— moiety. In embodiments, L⁴ is not —OC(O)—.

In embodiments, the compound has the formula:

L¹, L², L³, L⁴, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹⁴are as described herein. In embodiments, the compound has the formula:

L¹, L², L³, L⁴, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹⁴ are asdescribed herein. In embodiments, the compound has the formula:

L¹, L², L³, L⁴, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹⁴are as described herein. In embodiments, the compound has the formula:

L¹, L², L³, L⁴, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹⁴ are asdescribed herein. In embodiments, the compound has the formula:

L¹, L², L³, L⁴, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹² and R¹⁴are as described herein. In embodiments, the compound has the formula:

L¹, L², L³, L⁴, R², R³, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and R¹⁴ are asdescribed herein.

In embodiments, R¹⁴ is independently hydrogen, halogen, —CF₃, —CCl₃,—CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, R⁴⁴-substitutedor unsubstituted alkyl, R⁴⁴-substituted or unsubstituted heteroalkyl,R⁴⁴-substituted or unsubstituted cycloalkyl, R⁴⁴-substituted orunsubstituted heterocycloalkyl, R⁴⁴-substituted or unsubstituted aryl,R⁴⁴-substituted or unsubstituted heteroaryl, or a polymer. Inembodiments, R¹⁴ is a polymer (e.g., a monovalent polymer). Inembodiments, R¹⁴ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or—SO₄H. In embodiments, R¹⁴ is independently —SO₃H. In embodiments, R¹⁴is independently —PO₃H. In embodiments, R¹⁴ is independently —SO₂NH₂. Inembodiments, R¹⁴ is independently —SO₄H. In embodiments, R¹⁴ isindependently —PO₄H. In embodiments, when L¹⁴ is a bond, R¹⁴ is not—COOH. In embodiments, when L¹⁴ is a bond, R¹⁴ is not —C(O)NH.

R⁴⁴ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂,—CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl,—OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃,—OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R⁴⁴ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or—SO₄H. In embodiments, R⁴⁴ is independently —SO₃H. In embodiments, R⁴⁴is independently —PO₃H. In embodiments, R⁴⁴ is independently —SO₂NH₂. Inembodiments, R⁴⁴ is independently —SO₄H. In embodiments, R⁴⁴ isindependently —PO₄H.

In embodiments, L⁴ is independently a bond, —S(O)₂—, —NH—, —O—, —S—,—C(O)—, —C(O)NR⁵⁴—, —NR⁵⁴C(O)—, —NR⁵⁴C(O)NR^(54A)—, —S(O)₂NR⁵⁴—,—NR⁵⁴S(O)₂—, R⁵⁴-substituted or unsubstituted alkylene, R⁵⁴-substitutedor unsubstituted heteroalkylene, R⁵⁴-substituted or unsubstitutedcycloalkylene, R⁵⁴-substituted or unsubstituted heterocycloalkylene,R⁵⁴-substituted or unsubstituted arylene, or R⁵⁴-substituted orunsubstituted heteroarylene.

In embodiments, L⁴ is independently

and R⁵⁴ is as described herein, including in embodiments. Inembodiments, L⁴ is independently

and R⁵⁴ is as described herein, including in embodiments. Inembodiments, L⁴ is independently

and R⁵⁴ is as described herein, including in embodiments. Inembodiments, L⁴ is independently

In embodiments, L⁴ is independently

and R⁵⁴ is as described herein, including in embodiments.

In embodiments, R⁵⁴ is independently halogen, —CF₃, —CCl₃, —CI₃, —CBr₃,—CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F,—OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃,—OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl. In embodiments, R⁵⁴ is independentlysubstituted or unsubstituted C₁ alkyl. In embodiments, R⁵⁴ isindependently substituted or unsubstituted C₂ alkyl. In embodiments, R⁵⁴is independently substituted or unsubstituted C₃ alkyl. In embodiments,R⁵⁴ is independently substituted or unsubstituted C₄ alkyl. Inembodiments, R⁵⁴ is independently substituted or unsubstituted C₅ alkyl.In embodiments, R⁵⁴ is independently substituted or unsubstituted C₆alkyl. In embodiments, R⁵⁴ is independently substituted C₁ alkyl. Inembodiments, R⁵⁴ is independently substituted C₂ alkyl. In embodiments,R⁵⁴ is independently substituted C₃ alkyl. In embodiments, R⁵⁴ isindependently substituted C₄ alkyl. In embodiments, R⁵⁴ is independentlysubstituted C₅ alkyl. In embodiments, R⁵⁴ is independently substitutedC₆ alkyl. In embodiments, R⁵⁴ is independently unsubstituted C₁ alkyl.In embodiments, R⁵⁴ is independently unsubstituted C₂ alkyl. Inembodiments, R⁵⁴ is independently unsubstituted C₃ alkyl. Inembodiments, R⁵⁴ is independently unsubstituted C₄ alkyl. Inembodiments, R⁵⁴ is independently unsubstituted C₅ alkyl. Inembodiments, R⁵⁴ is independently unsubstituted C₆ alkyl. Inembodiments, R⁵⁴ is not hydrogen.

In embodiments, R^(54A) is independently halogen, —CF₃, —CCl₃, —CI₃,—CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, R^(54A) is independently substituted orunsubstituted C₁ alkyl. In embodiments, R^(54A) is independentlysubstituted or unsubstituted C₂ alkyl. In embodiments, R^(54A) isindependently substituted or unsubstituted C₃ alkyl. In embodiments,R^(54A) is independently substituted or unsubstituted C₄ alkyl. Inembodiments, R^(54A) is independently substituted or unsubstituted C₅alkyl. In embodiments, R^(54A) is independently substituted orunsubstituted C₆ alkyl. In embodiments, R^(54A) is independentlysubstituted C₁ alkyl. In embodiments, R^(54A) is independentlysubstituted C₂ alkyl. In embodiments, R^(54A) is independentlysubstituted C₃ alkyl. In embodiments, R^(54A) is independentlysubstituted C₄ alkyl. In embodiments, R^(54A) is independentlysubstituted C₅ alkyl. In embodiments, R^(54A) is independentlysubstituted C₆ alkyl. In embodiments, R^(54A) is independentlyunsubstituted C₁ alkyl. In embodiments, R^(54A) is independentlyunsubstituted C₂ alkyl. In embodiments, R^(54A) is independentlyunsubstituted C₃ alkyl. In embodiments, R^(54A) is independentlyunsubstituted C₄ alkyl. In embodiments, R^(54A) is independentlyunsubstituted C₅ alkyl. In embodiments, R^(54A) is independentlyunsubstituted C₆ alkyl. In embodiments, R^(54A) is not hydrogen.

In embodiments, R⁵⁴ is independently halogen, —CF₃, —CCl₃, —CI₃, —CBr₃,—CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F,—OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃,—OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, R⁵⁵-substituted orunsubstituted alkyl, R⁵⁵-substituted or unsubstituted heteroalkyl,R⁵⁵-substituted or unsubstituted cycloalkyl, R⁵⁵-substituted orunsubstituted heterocycloalkyl, R⁵⁵-substituted or unsubstituted aryl,or R⁵⁵-substituted or unsubstituted heteroaryl.

In embodiments, R^(54A) is independently halogen, —CF₃, —CCl₃, —CI₃,—CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃,R^(55A)-substituted or unsubstituted alkyl, R^(55A)-substituted orunsubstituted heteroalkyl, R^(55A)-substituted or unsubstitutedcycloalkyl, R^(55A)-substituted or unsubstituted heterocycloalkyl,R^(55A)-substituted or unsubstituted aryl, or R^(55A)-substituted orunsubstituted heteroaryl.

R⁵⁵ and R^(55A) are each independently oxo, halogen, —CF₃, —CCl₃, —CI₃,—CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstitutedalkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstitutedheteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6membered). In embodiments, R⁵⁵ is independently —PO₃H, —PO₄H, —SO₂NH₂,—SO₃H, or —SO₄H. In embodiments, R⁵⁵ is independently —SO₃H. Inembodiments, R⁵⁵ is independently —PO₃H. In embodiments, R⁵⁵ isindependently —SO₂NH₂. In embodiments, R⁵⁵ is independently —SO₄H. Inembodiments, R^(55A) is independently —PO₃H, —SO₂NH₂, —SO₃H, or —SO₄H.In embodiments, R^(55A) is independently —SO₃H. In embodiments, R^(55A)is independently —PO₃H. In embodiments, R^(55A) is independently—SO₂NH₂. In embodiments, R^(55A) is independently —SO₄H.

In embodiments, R¹⁴ is independently a polymer. In embodiments, R¹⁴ isindependently a monovalent PEG polymer. In embodiments, R¹⁴ is

wherein n1 is an integer from 1 to 30. In embodiments, n1 isindependently 1. In embodiments, n1 is independently 2. In embodiments,n1 is independently 3. In embodiments, n1 is independently 4. Inembodiments, n1 is independently 5. In embodiments, n1 is independently6. In embodiments, n1 is independently 7. In embodiments, n1 isindependently 8. In embodiments, n1 is independently 9. In embodiments,n1 is independently 10. In embodiments, n1 is independently 11. Inembodiments, n1 is independently 12. In embodiments, n1 is independently13. In embodiments, n1 is independently 14. In embodiments, n1 isindependently 15. In embodiments, n1 is independently 16. Inembodiments, n1 is independently 17. In embodiments, n1 is independently18. In embodiments, n1 is independently 19. In embodiments, n1 isindependently 20. In embodiments, n1 is independently 21. Inembodiments, n1 is independently 22. In embodiments, n1 is independently23. In embodiments, n1 is independently 24. In embodiments, n1 isindependently 25. In embodiments, n1 is independently 26. Inembodiments, n1 is independently 27. In embodiments, n1 is independently28. In embodiments, n1 is independently 29. In embodiments, n1 isindependently 30. In embodiments, n1 is independently an integer from 1to 6. In embodiments, n1 is independently an integer from 10 to 20. Inembodiments, n1 is independently an integer from 5 to 15. Inembodiments, R¹⁴ is independently

In embodiments, R¹⁴ is independently

In embodiments, -L⁴-R¹⁴ is independently

wherein n1 is as described herein (e.g., an integer from 5 to 15).

In embodiments, -L⁴-R¹⁴ is

wherein R⁵⁴ and n1 are as described herein (e.g., an integer from 5 to15). In embodiments, -L⁴-R¹⁴ is

wherein n1 is as described herein (e.g., an integer from 5 to 15).

In embodiments, -L⁴-R¹⁴ is

wherein R⁵⁴ is as described herein. In embodiments, -L⁴-R¹⁴ is

wherein R⁵⁴ is as described herein. In embodiments, -L⁴-R¹⁴ is

wherein R⁵⁴ is as described herein. In embodiments, -L⁴-R¹⁴ is

In embodiments, -L⁴-R¹⁴ is not —COOH. In embodiments, -L⁴-R¹⁴ is not—CH₃.

In embodiments, L³ is independently a bond, —S(O)₂—, —NH—, —O—, —S—,—C(O)—, —C(O)NR¹—, —NR¹C(O)—, —NR¹C(O)NR^(1A)—, —S(O)₂NR¹—, —NR¹S(O)₂—,R¹-substituted or unsubstituted alkylene, R¹-substituted orunsubstituted heteroalkylene, R¹-substituted or unsubstitutedcycloalkylene, R¹-substituted or unsubstituted heterocycloalkylene,R¹-substituted or unsubstituted arylene, or R¹-substituted orunsubstituted heteroarylene.

In embodiments, L³ is independently

and R¹ is as described herein, including in embodiments. In embodiments,L³ is independently

and R¹ is as described herein, including in embodiments. In embodiments,L³ is independently

and R¹ is as described herein, including in embodiments. In embodiments,L³ is independently

In embodiments, L³ is independently

and R¹ is as described herein, including in embodiments. In embodiments,L³ is independently

wherein z1 is independently an integer from 1 to 6, and R³¹ is asdescribed herein, including embodiments. In embodiments, z1 isindependently an integer from 1 to 3. In embodiments, z1 isindependently 1. In embodiments, z1 is independently 2. In embodiments,z1 is independently 3. In embodiments, z1 is independently 4. Inembodiments, z1 is independently 5. In embodiments, z1 is independently6. In embodiments, R³¹ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or—SO₄H. In embodiments, R³¹ is independently —SO₃H. In embodiments, R³¹is independently —PO₃H. In embodiments, R³¹ is independently —SO₂NH₂. Inembodiments, R³¹ is independently —PO₄H. In embodiments, R³¹ isindependently —SO₄H.

In embodiments, L¹ and L² are each independently a bond, —S(O)₂—,—S(O)₂NH—, —NHS(O)₂—, —NH—, —O—, —S—, —C(O)—, —C(O)NH—, —NHC(O)—,—NHC(O)NH—, —C(O)O—, —OC(O)—, substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, substitutedor unsubstituted heteroarylene, or a divalent polymer. In embodiments,L¹ and L² are each independently a divalent polymer. In embodiments, L¹and L² are each independently divalent polyethylene glycol (PEG).

In embodiments, L¹ and L² are each independently a bond, —S(O)₂—, —NH—,—O—, —S—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, substituted or unsubstituted heteroarylene, or a divalentpolymer. In embodiments, when L³ is a bond, L¹ is not —C(O)O— or—OC(O)—. In embodiments, when L³ is a bond, L² is not —C(O)O— or—OC(O)—.

In embodiments, L¹ is independently a bond, —S(O)₂—, —S(O)₂NH—,—NHS(O)₂—, —NH—, —O—, —S—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—,—C(O)O—, —OC(O)—, R^(5′)-substituted or unsubstituted alkylene,R⁵¹-substituted or unsubstituted heteroalkylene, R⁵¹-substituted orunsubstituted cycloalkylene, R⁵¹-substituted or unsubstitutedheterocycloalkylene, R⁵¹-substituted or unsubstituted arylene,R⁵¹-substituted or unsubstituted heteroarylene, or a divalent polymer.In embodiments, L¹ is independently a divalent polymer. In embodiments,L¹ is independently divalent polyethylene glycol (PEG).

In embodiments, L¹ is independently a bond, —S(O)₂—, —NH—, —O—, —S—,—C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—,R⁵¹-substituted or unsubstituted alkylene, R⁵¹-substituted orunsubstituted heteroalkylene, R⁵¹-substituted or unsubstitutedcycloalkylene, R⁵¹-substituted or unsubstituted heterocycloalkylene,R⁵¹-substituted or unsubstituted arylene, R⁵¹-substituted orunsubstituted heteroarylene, or a divalent polymer.

R⁵¹ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂,—CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl,—OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃,—OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, L² is independently a bond, —S(O)₂—, —S(O)₂NH—,—NHS(O)₂—, —NH—, —O—, —S—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—,—C(O)O—, —OC(O)—, R⁵²-substituted or unsubstituted alkylene,R⁵²-substituted or unsubstituted heteroalkylene, R⁵²-substituted orunsubstituted cycloalkylene, R⁵²-substituted or unsubstitutedheterocycloalkylene, R⁵²-substituted or unsubstituted arylene,R⁵²-substituted or unsubstituted heteroarylene, or a divalent polymer.In embodiments, L² is independently a divalent polymer. In embodiments,L² is independently divalent polyethylene glycol (PEG).

In embodiments, L² is independently a bond, —S(O)₂—, —NH—, —O—, —S—,—C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—,R⁵²-substituted or unsubstituted alkylene, R⁵²-substituted orunsubstituted heteroalkylene, R⁵²-substituted or unsubstitutedcycloalkylene, R⁵²-substituted or unsubstituted heterocycloalkylene,R⁵²-substituted or unsubstituted arylene, R⁵²-substituted orunsubstituted heteroarylene, or a divalent polymer.

R⁵² is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂,—CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl,—OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃,—OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, L¹ and L² are each independently substituted orunsubstituted alkylene (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂),substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),substituted or unsubstituted cycloalkylene (e.g., C₃-C₈, C₃-C₆, C₄-C₆,or C₅-C₆), substituted or unsubstituted heterocycloalkylene (e.g., 3 to8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), substituted or unsubstituted arylene (e.g., C₆-C₁₀ orphenylene), or substituted or unsubstituted heteroarylene (e.g., 5 to 10membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, L¹ and L² are each independently substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkylene, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkylene,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedcycloalkylene, substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group) orunsubstituted heterocycloalkylene, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted arylene, or substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroarylene.

In embodiments, L¹ and L² are each independently unsubstituted alkylene,unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstitutedheterocycloalkylene, unsubstituted arylene, or unsubstitutedheteroarylene.

In embodiments, L¹ is independently a bond, —C(O)—, —C(O)NH—, —NHC(O)—,—NHC(O)NH—, —C(O)O—, —OC(O)—, substituted or unsubstituted C₁-C₆alkylene. In embodiments, L¹ is independently substituted orunsubstituted C₁-C₆ alkylene.

In embodiments, L² is independently a bond, —C(O)—, —C(O)NH—, —NHC(O)—,—NHC(O)NH—, —C(O)O—, —OC(O)—, substituted or unsubstituted C₁-C₆alkylene. In embodiments, L² is independently substituted orunsubstituted C₁-C₆ alkylene. In embodiments, L² is independently abond, —C(O)—, —C(O)O—, or —OC(O)—. In embodiments, L² is independently abond. In embodiments, L² is independently —C(O)—. In embodiments, L² isindependently —C(O)O—. In embodiments, L² is independently —OC(O)—.

In embodiments, L¹ includes an orthogonally cleavable linker,photocleavable linker, or cleavable linker. In embodiments, L¹ is anorthogonally cleavable linker, photocleavable linker, or cleavablelinker. In embodiments, L² includes an orthogonally cleavable linker,photocleavable linker, or cleavable linker. In embodiments, L² is anorthogonally cleavable linker, photocleavable linker, or cleavablelinker.

In embodiments, L¹ is independently a polymer. In embodiments, L¹includes a polymer. In embodiments, L¹ includes PEG. In embodiments, L¹includes the divalent moiety having the formula:

wherein n is an integer from 1 to 30. In embodiments, L² isindependently a polymer. In embodiments, L² includes a polymer. Inembodiments, L² includes PEG. In embodiments, L² includes the divalentmoiety

wherein n is as described herein. In embodiments, n is independently 1.In embodiments, n is independently 2. In embodiments, n is independently3. In embodiments, n is independently an integer from 1 to 6.

In embodiments, -L¹-L²-R⁸ is

In embodiments, L¹ is —C(CH₃)₂CH₂NHC(O)—,

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, L¹ is

In embodiments, -L¹-L²- is

In embodiments, -L¹-L²- is

In embodiments, -L¹-L²- is

In embodiments, L² is —C(CH₃)₂CH₂NHC(O)—,

In embodiments, L² is

In embodiments, L² is

In embodiments, L² is

In embodiments, -L¹-L²- is

In embodiments, -L¹-L²- is

In embodiments, -L¹-L²- is

In embodiments, -L¹-L²- is

In embodiments, -L¹-L²- is

In embodiments, -L¹-L²- is

In embodiments, -L¹-L²- is

In embodiments, -L¹-L²- is

In embodiments, L¹ is L^(1A)-L^(1B)-L^(1C)-L^(1D)-L^(1E). L^(1A),L^(1B), L^(1C), L^(1D), or L^(1E) are independently a bond, —SS—, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted alkylene (e.g., alkylene, alkenylene, or alkynylene),substituted (e.g., substituted with a substituent group, size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroalkylene (e.g., heteroalkylene, heteroalkenylene, orheteroalkynylene), substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heterocycloalkylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted arylene, or substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted heteroarylene; wherein atleast one of L^(1A), L^(1B), L^(1C), L^(1D), and L^(1E) is not a bond.

In embodiments, L^(1A), L^(1B), L^(1C), L^(1D), or L^(1E) areindependently a bond, —NN—, —NHC(O)—, —C(O)NH—, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted alkylene (e.g., alkylene,alkenylene, or alkynylene), substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted heterocycloalkylene,substituted (e.g., substituted with a substituent group, size-limitedsubstituent group, or lower substituent group) or unsubstituted arylene,or substituted (e.g., substituted with a substituent group, size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroarylene; wherein at least one of L^(1A), L^(1B), L^(1C), L^(1D),and L^(1E) is not a bond.

In embodiments, L^(1A) is independently a bond, —SS—, —NN—, —NHC(O)—,—C(O)NH—, R^(51A)-substituted or unsubstituted alkylene,R^(51A)-substituted or unsubstituted heteroalkylene, R^(51A)-substitutedor unsubstituted cycloalkylene, R^(51A)-substituted or unsubstitutedheterocycloalkylene, R^(51A)-substituted or unsubstituted arylene, orR^(51A)-substituted or unsubstituted heteroarylene.

In embodiments, L^(1B) is independently a bond, —SS—, —NN—, —NHC(O)—,—C(O)NH—, R^(51B)-substituted or unsubstituted alkylene,R^(51B)-substituted or unsubstituted heteroalkylene, R^(51B)-substitutedor unsubstituted cycloalkylene, R^(51B)-substituted or unsubstitutedheterocycloalkylene, R^(51B)-substituted or unsubstituted arylene, orR^(51B)-substituted or unsubstituted heteroarylene.

In embodiments, L^(1C) is independently a bond, —SS—, —NN—, —NHC(O)—,—C(O)NH—, R^(51C)-substituted or unsubstituted alkylene,R^(51C)-substituted or unsubstituted heteroalkylene, R^(51C)-substitutedor unsubstituted cycloalkylene, R^(51C)-substituted or unsubstitutedheterocycloalkylene, R^(51C)-substituted or unsubstituted arylene, orR^(51C)-substituted or unsubstituted heteroarylene.

In embodiments, L^(1D) is independently a bond, —SS—, —NN—, —NHC(O)—,—C(O)NH—, R^(51D)-substituted or unsubstituted alkylene,R^(51D)-substituted or unsubstituted heteroalkylene, R^(51D)-substitutedor unsubstituted cycloalkylene, R^(51D)-substituted or unsubstitutedheterocycloalkylene, R^(51D)-substituted or unsubstituted arylene, orR^(51D)-substituted or unsubstituted heteroarylene.

In embodiments, L^(1E) is independently a bond, —SS—, —NN—, —NHC(O)—,—C(O)NH—, R^(51E)-substituted or unsubstituted alkylene,R^(51E)-substituted or unsubstituted heteroalkylene, R^(51E)-substitutedor unsubstituted cycloalkylene, R^(51E)-substituted or unsubstitutedheterocycloalkylene, R^(51E)-substituted or unsubstituted arylene, orR^(51E)-substituted or unsubstituted heteroarylene.

R^(51A), R^(51B), R^(51C), R^(51D), and R^(51E) are each independentlyoxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂,—CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂,—OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, L¹ is L^(1A)-L^(1B)-L^(1C)-L^(1D)-L^(1E); and L^(1A),L^(1B), L^(1C), L^(1D), or L^(1E) are independently a bond, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₁-C₂₀ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 20 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₂₀ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 20 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₆-C₂₀ arylene, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 20 membered heteroarylene; wherein at leastone of L^(1A), L^(1B), L^(1C), L^(1D), and L^(1E) is not a bond.

In embodiments, L¹ is L^(1A)-L^(1B)-L^(1C)-L^(1D)-L^(1E); and L^(1A),L^(1B), L^(1C), L^(1D), or L^(1E) are independently a bond, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₁-C₁₀ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 10 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₈ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 8 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₆-C₁₀ arylene, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 10 membered heteroarylene; wherein at leastone of L^(1A), L^(1B), L^(1C), L^(1D), and L^(1E) is not a bond.

In embodiments, L¹ is L^(1A)-L^(1B)-L^(1C)-L^(1D)-L^(1E); and L^(1A),L^(1B), L^(1C), L^(1D), or L^(1E) are independently a bond, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₁-C₆ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 6 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₆ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 6 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted phenyl, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 6 membered heteroarylene; wherein at leastone of L^(1A), L^(1B), L^(1C), L^(1D), and L^(1E) is not a bond.

In embodiments, L¹ is L^(1A)-L^(1B)-L^(1C)-L^(1D)-L^(1E); wherein L^(1A)is a bond, —NN—, —NHC(O)—, —C(O)NH—, substituted (e.g., substituted witha substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted alkylene (e.g., alkylene,alkenylene, or alkynylene), substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene); L^(1B) is a bond, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heterocycloalkylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted arylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted heteroarylene; L^(1C) is abond, —NN—, —NHC(O)—, —C(O)NH—, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted cycloalkylene, substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted arylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted heteroarylene;L^(1D) is a bond, —NN—, —NHC(O)—, —C(O)NH—, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted alkylene (e.g., alkylene,alkenylene, or alkynylene), substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene); and L^(1E) is a bond, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted alkylene (e.g., alkylene, alkenylene, or alkynylene),substituted (e.g., substituted with a substituent group, size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroalkylene (e.g., heteroalkylene, heteroalkenylene, orheteroalkynylene), substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heterocycloalkylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted arylene, or substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted heteroarylene; wherein atleast one of L^(1A), L^(1B), L^(1C), L^(1D), and L^(1E) is not a bond.

In embodiments, L¹ is a bond, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted heteroalkylene (e.g., heteroalkylene, heteroalkenylene, orheteroalkynylene), substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heterocycloalkylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted arylene, or substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted heteroarylene.

In embodiments, L¹ is a bond, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted C₁-C₂₀ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 20 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₂₀ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 20 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₆-C₂₀ arylene, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 20 membered heteroarylene.

In embodiments, L¹ is a bond, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted C₁-C₈ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 8 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₈ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 8 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₆-C₁₀ arylene, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 10 membered heteroarylene.

In embodiments, L¹ is a bond, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted C₁-C₆ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 6 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₆ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 6 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted phenyl, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 6 membered heteroarylene.

In embodiments, L¹ is a substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 3 to 10 membered heteroalkylene (e.g.,heteroalkylene, heteroalkenylene, or heteroalkynylene). In embodiments,L¹ is a substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 3 to 8 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene). In embodiments, L¹ is asubstituted (e.g., substituted with a substituent group, size-limitedsubstituent group, or lower substituent group) or unsubstituted 3 to 6membered heteroalkylene (e.g., heteroalkylene, heteroalkenylene, orheteroalkynylene).

In embodiments, L¹ is substituted or unsubstituted methylene. Inembodiments, L¹ is substituted or unsubstituted C₂ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₃ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₄ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₅ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₆ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₇ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₈ alkylene. Inembodiments, L¹ is substituted methylene. In embodiments, L¹ issubstituted C₂ alkylene. In embodiments, L¹ is substituted C₃ alkylene.In embodiments, L¹ is substituted C₄ alkylene. In embodiments, L¹ issubstituted C₅ alkylene. In embodiments, L¹ is substituted C₆ alkylene.In embodiments, L¹ is substituted C₇ alkylene. In embodiments, L¹ issubstituted C₈ alkylene. In embodiments, L¹ is an unsubstitutedmethylene. In embodiments, L¹ is an unsubstituted C₂ alkylene. Inembodiments, L¹ is an unsubstituted C₃ alkylene. In embodiments, L¹ isan unsubstituted C₄ alkylene. In embodiments, L¹ is an unsubstituted C₅alkylene. In embodiments, L¹ is an unsubstituted C₆ alkylene. Inembodiments, L¹ is an unsubstituted C₇ alkylene. In embodiments, L¹ isan unsubstituted C₈ alkylene.

In embodiments, L¹ is substituted or unsubstituted C₁-C₆ alkylene. Inembodiments, L¹ is substituted C₁-C₆ alkylene. In embodiments, L¹ isunsubstituted C₁-C₆ alkylene. In embodiments, L¹ is substituted orunsubstituted C₂-C₆ alkylene. In embodiments, L¹ is substituted C₂-C₆alkylene. In embodiments, L¹ is unsubstituted C₂-C₆ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₁ alkylene. Inembodiments, L¹ is substituted C₁ alkylene. In embodiments, L¹ isunsubstituted C₁ alkylene. In embodiments, L¹ is substituted orunsubstituted C₂ alkylene. In embodiments, L¹ is substituted C₂alkylene. In embodiments, L¹ is unsubstituted C₂ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₃ alkylene. Inembodiments, L¹ is substituted C₃ alkylene. In embodiments, L¹ isunsubstituted C₃ alkylene. In embodiments, L¹ is substituted orunsubstituted C₄ alkylene. In embodiments, L¹ is substituted C₄alkylene. In embodiments, L¹ is unsubstituted C₄ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₅ alkylene. Inembodiments, L¹ is substituted C₅ alkylene. In embodiments, L¹ isunsubstituted C₅ alkylene. In embodiments, L¹ is substituted orunsubstituted C₆ alkylene. In embodiments, L¹ is substituted C₆alkylene. In embodiments, L¹ is unsubstituted C₆ alkylene.

In embodiments, L¹ is substituted or unsubstituted C₉ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₁₀ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₁₁ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₁₂ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₁₃ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₁₄ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₁₈ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₁₆ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₁₇ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₁₈ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₁₉ alkylene. Inembodiments, L¹ is substituted or unsubstituted C₂₀ alkylene.

In embodiments, L¹ is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L¹ is substituted 2 to 8 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L¹ is substituted 2 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 2 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 3membered heteroalkylene. In embodiments, L¹ is substituted 3 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 3 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 4membered heteroalkylene. In embodiments, L¹ is substituted 4 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 4 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 5membered heteroalkylene. In embodiments, L¹ is substituted 5 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 5 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 6membered heteroalkylene. In embodiments, L¹ is substituted 6 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 6 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 7membered heteroalkylene. In embodiments, L¹ is substituted 7 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 7 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 8membered heteroalkylene. In embodiments, L¹ is substituted 8 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 8 memberedheteroalkylene.

In embodiments, L¹ is substituted or unsubstituted 9 memberedheteroalkylene. In embodiments, L¹ is substituted 9 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 9 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 10membered heteroalkylene. In embodiments, L¹ is substituted 10 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 10 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 11membered heteroalkylene. In embodiments, L¹ is substituted 11 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 11 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 12membered heteroalkylene. In embodiments, L¹ is substituted 12 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 12 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 13membered heteroalkylene. In embodiments, L¹ is substituted 13 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 13 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 14membered heteroalkylene. In embodiments, L¹ is substituted 14 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 14 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 15membered heteroalkylene. In embodiments, L¹ is substituted 15 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 15 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 16membered heteroalkylene. In embodiments, L¹ is substituted 16 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 16 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 17membered heteroalkylene. In embodiments, L¹ is substituted 17 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 17 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 18membered heteroalkylene. In embodiments, L¹ is substituted 18 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 18 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 19membered heteroalkylene. In embodiments, L¹ is substituted 19 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 19 memberedheteroalkylene. In embodiments, L¹ is substituted or unsubstituted 20membered heteroalkylene. In embodiments, L¹ is substituted 20 memberedheteroalkylene. In embodiments, L¹ is unsubstituted 20 memberedheteroalkylene.

In embodiments, L¹ is substituted or unsubstituted C₄-C₆ cycloalkylene.In embodiments, L¹ is substituted C₄-C₆ cycloalkylene. In embodiments,L¹ is substituted C₄-C₆ cycloalkylene. In embodiments, L¹ is substitutedor unsubstituted C₄ cycloalkylene. In embodiments, L¹ is substituted C₄cycloalkylene. In embodiments, L¹ is substituted C₄ cycloalkylene. Inembodiments, L¹ is substituted or unsubstituted C₅ cycloalkylene. Inembodiments, L¹ is substituted C₅ cycloalkylene. In embodiments, L¹ issubstituted C₅ cycloalkylene.

In embodiments, L¹ is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L¹ is substituted 5 to 6 memberedheterocycloalkylene. In embodiments, L¹ is unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L¹ is substituted or unsubstituted5 membered heterocycloalkylene. In embodiments, L¹ is substituted 5membered heterocycloalkylene. In embodiments, L¹ is unsubstituted 5membered heterocycloalkylene. In embodiments, L¹ is substituted orunsubstituted 6 membered heterocycloalkylene. In embodiments, L¹ issubstituted 6 membered heterocycloalkylene. In embodiments, L¹ isunsubstituted 6 membered heterocycloalkylene.

In embodiments, L¹ is substituted or unsubstituted phenylene. Inembodiments, L¹ is substituted phenylene. In embodiments, L¹ isunsubstituted phenylene.

In embodiments, L¹ is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L¹ is substituted 5 to 6 memberedheteroarylene. In embodiments, L¹ is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L¹ is substituted or unsubstituted 5membered heteroarylene. In embodiments, L¹ is substituted 5 memberedheteroarylene. In embodiments, L¹ is unsubstituted 5 memberedheteroarylene. In embodiments, L¹ is substituted or unsubstituted 6membered heteroarylene. In embodiments, L¹ is substituted 6 memberedheteroarylene. In embodiments, L¹ is unsubstituted 6 memberedheteroarylene.

In embodiments, L¹ is a polymer.

In embodiments, L^(1A) is substituted or unsubstituted methylene. Inembodiments, L^(1A) is substituted or unsubstituted C₂ alkylene. Inembodiments, L^(1A) is substituted or unsubstituted C₃ alkylene. Inembodiments, L^(1A) is substituted or unsubstituted C₄ alkylene. Inembodiments, L^(1A) is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(1A) is substituted or unsubstituted C₆ alkylene. Inembodiments, L^(1A) is substituted or unsubstituted C₇ alkylene. Inembodiments, L^(1A) is substituted or unsubstituted C₈ alkylene. Inembodiments, L^(1A) is substituted methylene. In embodiments, L^(1A) issubstituted C₂ alkylene. In embodiments, L^(1A) is substituted C₃alkylene. In embodiments, L^(1A) is substituted C₄ alkylene. Inembodiments, L^(1A) is substituted C₅ alkylene. In embodiments, L^(1A)is substituted C₆ alkylene. In embodiments, L^(1A) is substituted C₇alkylene. In embodiments, L^(1A) is substituted C₈ alkylene. Inembodiments, L^(1A) is an unsubstituted methylene. In embodiments,L^(1A) is an unsubstituted C₂ alkylene. In embodiments, L^(1A) is anunsubstituted C₃ alkylene. In embodiments, L^(1A) is an unsubstituted C₄alkylene. In embodiments, L^(1A) is an unsubstituted C₅ alkylene. Inembodiments, L^(1A) is an unsubstituted C₆ alkylene. In embodiments,L^(1A) is an unsubstituted C₇ alkylene. In embodiments, L^(1A) is anunsubstituted C₈ alkylene.

In embodiments, L^(1A) is substituted or unsubstituted C₁-C₆ alkylene.In embodiments, L^(1A) is substituted C₁-C₆ alkylene. In embodiments,L^(1A) is unsubstituted C₁-C₆ alkylene. In embodiments, L^(1A) issubstituted or unsubstituted C₂-C₆ alkylene. In embodiments, L^(1A) issubstituted C₂-C₆ alkylene. In embodiments, L^(1A) is unsubstitutedC₂-C₆ alkylene. In embodiments, L^(1A) is substituted or unsubstitutedC₁ alkylene. In embodiments, L^(1A) is substituted C₁ alkylene. Inembodiments, L^(1A) is unsubstituted C₁ alkylene. In embodiments, L^(1A)is substituted or unsubstituted C₂ alkylene. In embodiments, L^(1A) issubstituted C₂ alkylene. In embodiments, L^(1A) is unsubstituted C₂alkylene. In embodiments, L^(1A) is substituted or unsubstituted C₃alkylene. In embodiments, L^(1A) is substituted C₃ alkylene. Inembodiments, L^(1A) is unsubstituted C₃ alkylene. In embodiments, L^(1A)is substituted or unsubstituted C₄ alkylene. In embodiments, L^(1A) issubstituted C₄ alkylene. In embodiments, L^(1A) is unsubstituted C₄alkylene. In embodiments, L^(1A) is substituted or unsubstituted C₅alkylene. In embodiments, L^(1A) is substituted C₅ alkylene. Inembodiments, L^(1A) is unsubstituted C₅ alkylene. In embodiments, L^(1A)is substituted or unsubstituted C₆ alkylene. In embodiments, L^(1A) issubstituted C₆ alkylene. In embodiments, L^(1A) is unsubstituted C₆alkylene.

In embodiments, L^(1A) is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1A) is substituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1A) is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1A) is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L^(1A) is substituted 2membered heteroalkylene. In embodiments, L^(1A) is unsubstituted 2membered heteroalkylene. In embodiments, L^(1A) is substituted orunsubstituted 3 membered heteroalkylene. In embodiments, L^(1A) issubstituted 3 membered heteroalkylene. In embodiments, L^(1A) isunsubstituted 3 membered heteroalkylene. In embodiments, L^(1A) issubstituted or unsubstituted 4 membered heteroalkylene. In embodiments,L^(1A) is substituted 4 membered heteroalkylene. In embodiments, L^(1A)is unsubstituted 4 membered heteroalkylene. In embodiments, L^(1A) issubstituted or unsubstituted 5 membered heteroalkylene. In embodiments,L^(1A) is substituted 5 membered heteroalkylene. In embodiments, L^(1A)is unsubstituted 5 membered heteroalkylene. In embodiments, L^(1A) issubstituted or unsubstituted 6 membered heteroalkylene. In embodiments,L^(1A) is substituted 6 membered heteroalkylene. In embodiments, L^(1A)is unsubstituted 6 membered heteroalkylene.

In embodiments, L^(1A) is substituted or unsubstituted C₄-C₆cycloalkylene. In embodiments, L^(1A) is substituted C₄-C₆cycloalkylene. In embodiments, L^(1A) is substituted C₄-C₆cycloalkylene. In embodiments, L^(1A) is substituted or unsubstituted C₄cycloalkylene. In embodiments, L^(1A) is substituted C₄ cycloalkylene.In embodiments, L^(1A) is substituted C₄ cycloalkylene. In embodiments,L^(1A) is substituted or unsubstituted C₅ cycloalkylene. In embodiments,L^(1A) is substituted C₅ cycloalkylene. In embodiments, L^(1A) issubstituted C₅ cycloalkylene.

In embodiments, L^(1A) is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L^(1A) is substituted 5 to 6membered heterocycloalkylene. In embodiments, L^(1A) is unsubstituted 5to 6 membered heterocycloalkylene. In embodiments, L^(1A) is substitutedor unsubstituted 5 membered heterocycloalkylene. In embodiments, L^(1A)is substituted 5 membered heterocycloalkylene. In embodiments, L^(1A) isunsubstituted 5 membered heterocycloalkylene. In embodiments, L^(1A) issubstituted or unsubstituted 6 membered heterocycloalkylene. Inembodiments, L^(1A) is substituted 6 membered heterocycloalkylene. Inembodiments, L^(1A) is unsubstituted 6 membered heterocycloalkylene.

In embodiments, L^(1A) is substituted or unsubstituted phenylene. Inembodiments, L^(1A) is substituted phenylene. In embodiments, L^(1A) isunsubstituted phenylene.

In embodiments, L^(1A) is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(1A) is substituted 5 to 6 memberedheteroarylene. In embodiments, L^(1A) is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(1A) is substituted or unsubstituted 5membered heteroarylene. In embodiments, L^(1A) is substituted 5 memberedheteroarylene. In embodiments, L^(1A) is unsubstituted 5 memberedheteroarylene. In embodiments, L^(1A) is substituted or unsubstituted 6membered heteroarylene. In embodiments, L^(1A) is substituted 6 memberedheteroarylene. In embodiments, L^(1A) is unsubstituted 6 memberedheteroarylene.

In embodiments, L^(1A) is a polymer.

In embodiments, L^(1B) is substituted or unsubstituted methylene. Inembodiments, L^(1B) is substituted or unsubstituted C₂ alkylene. Inembodiments, L^(1B) is substituted or unsubstituted C₃ alkylene. Inembodiments, L^(1B) is substituted or unsubstituted C₄ alkylene. Inembodiments, L^(1B) is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(1B) is substituted or unsubstituted C₆ alkylene. Inembodiments, L^(1B) is substituted or unsubstituted C₇ alkylene. Inembodiments, L^(1B) is substituted or unsubstituted C₈ alkylene. Inembodiments, L^(1B) is substituted methylene. In embodiments, L^(1B) issubstituted C₂ alkylene. In embodiments, L^(1B) is substituted C₃alkylene. In embodiments, L^(1B) is substituted C₄ alkylene. Inembodiments, L^(1B) is substituted C₅ alkylene. In embodiments, L^(1B)is substituted C₆ alkylene. In embodiments, L^(1B) is substituted C₇alkylene. In embodiments, L^(1B) is substituted C₈ alkylene. Inembodiments, L^(1B) is an unsubstituted methylene. In embodiments,L^(1B) is an unsubstituted C₂ alkylene. In embodiments, L^(1B) is anunsubstituted C₃ alkylene. In embodiments, L^(1B) is an unsubstituted C₄alkylene. In embodiments, L^(1B) is an unsubstituted C₅ alkylene. Inembodiments, L^(1B) is an unsubstituted C₆ alkylene. In embodiments,L^(1B) is an unsubstituted C₇ alkylene. In embodiments, L^(1B) is anunsubstituted C₈ alkylene.

In embodiments, L^(1B) is substituted or unsubstituted C₁-C₆ alkylene.In embodiments, L^(1B) is substituted C₁-C₆ alkylene. In embodiments,L^(1B) is unsubstituted C₁-C₆ alkylene. In embodiments, L^(1B) issubstituted or unsubstituted C₂-C₆ alkylene. In embodiments, L^(1B) issubstituted C₂-C₆ alkylene. In embodiments, L^(1B) is unsubstitutedC₂-C₆ alkylene. In embodiments, L^(1B) is substituted or unsubstitutedC₁ alkylene. In embodiments, L^(1B) is substituted C₁ alkylene. Inembodiments, L^(1B) is unsubstituted C₁ alkylene. In embodiments, L^(1B)is substituted or unsubstituted C₂ alkylene. In embodiments, L^(1B) issubstituted C₂ alkylene. In embodiments, L^(1B) is unsubstituted C₂alkylene. In embodiments, L^(1B) is substituted or unsubstituted C₃alkylene. In embodiments, L^(1B) is substituted C₃ alkylene. Inembodiments, L^(1B) is unsubstituted C₃ alkylene. In embodiments, L^(1B)is substituted or unsubstituted C₄ alkylene. In embodiments, L^(1B) issubstituted C₄ alkylene. In embodiments, L^(1B) is unsubstituted C₄alkylene. In embodiments, L^(1B) is substituted or unsubstituted C₅alkylene. In embodiments, L^(1B) is substituted C₅ alkylene. Inembodiments, L^(1B) is unsubstituted C₅ alkylene. In embodiments, L^(1B)is substituted or unsubstituted C₆ alkylene. In embodiments, L^(1B) issubstituted C₆ alkylene. In embodiments, L^(1B) is unsubstituted C₆alkylene.

In embodiments, L^(1B) is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1B) is substituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1B) is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1B) is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L^(1B) is substituted 2membered heteroalkylene. In embodiments, L^(1B) is unsubstituted 2membered heteroalkylene. In embodiments, L^(1B) is substituted orunsubstituted 3 membered heteroalkylene. In embodiments, L^(1B) issubstituted 3 membered heteroalkylene. In embodiments, L^(1B) isunsubstituted 3 membered heteroalkylene. In embodiments, L^(1B) issubstituted or unsubstituted 4 membered heteroalkylene. In embodiments,L^(1B) is substituted 4 membered heteroalkylene. In embodiments, L^(1B)is unsubstituted 4 membered heteroalkylene. In embodiments, L^(1B) issubstituted or unsubstituted 5 membered heteroalkylene. In embodiments,L^(1B) is substituted 5 membered heteroalkylene. In embodiments, L^(1B)is unsubstituted 5 membered heteroalkylene. In embodiments, L^(1B) issubstituted or unsubstituted 6 membered heteroalkylene. In embodiments,L^(1B) is substituted 6 membered heteroalkylene. In embodiments, L^(1B)is unsubstituted 6 membered heteroalkylene.

In embodiments, L^(1B) is substituted or unsubstituted C₄-C₆cycloalkylene. In embodiments, L^(1B) is substituted C₄-C₆cycloalkylene. In embodiments, L^(1B) is substituted C₄-C₆cycloalkylene. In embodiments, L^(1B) is substituted or unsubstituted C₄cycloalkylene. In embodiments, L^(1B) is substituted C₄ cycloalkylene.In embodiments, L^(1B) is substituted C₄ cycloalkylene. In embodiments,L^(1B) is substituted or unsubstituted C₅ cycloalkylene. In embodiments,L^(1B) is substituted C₅ cycloalkylene. In embodiments, L^(1B) issubstituted C₅ cycloalkylene.

In embodiments, L^(1B) is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L^(1B) is substituted 5 to 6membered heterocycloalkylene. In embodiments, L^(1B) is unsubstituted 5to 6 membered heterocycloalkylene. In embodiments, L^(1B) is substitutedor unsubstituted 5 membered heterocycloalkylene. In embodiments, L^(1B)is substituted 5 membered heterocycloalkylene. In embodiments, L^(1B) isunsubstituted 5 membered heterocycloalkylene. In embodiments, L^(1B) issubstituted or unsubstituted 6 membered heterocycloalkylene. Inembodiments, L^(1B) is substituted 6 membered heterocycloalkylene. Inembodiments, L^(1B) is unsubstituted 6 membered heterocycloalkylene.

In embodiments, L^(1B) is substituted or unsubstituted phenylene. Inembodiments, L^(1B) is substituted phenylene. In embodiments, L^(1B) isunsubstituted phenylene.

In embodiments, L^(1B) is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(1B) is substituted 5 to 6 memberedheteroarylene. In embodiments, L^(1B) is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(1B) is substituted or unsubstituted 5membered heteroarylene. In embodiments, L^(1B) is substituted 5 memberedheteroarylene. In embodiments, L^(1B) is unsubstituted 5 memberedheteroarylene. In embodiments, L^(1B) is substituted or unsubstituted 6membered heteroarylene. In embodiments, L^(1B) is substituted 6 memberedheteroarylene. In embodiments, L^(1B) is unsubstituted 6 memberedheteroarylene.

In embodiments, L^(1C) is substituted or unsubstituted methylene. Inembodiments, L^(1C) is substituted or unsubstituted C₂ alkylene. Inembodiments, L^(1C) is substituted or unsubstituted C₃ alkylene. Inembodiments, L^(1C) is substituted or unsubstituted C₄ alkylene. Inembodiments, L^(1C) is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(1C) is substituted or unsubstituted C₆ alkylene. Inembodiments, L^(1C) is substituted or unsubstituted C₇ alkylene. Inembodiments, L^(1C) is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(1C) is substituted methylene. In embodiments, L^(1C) issubstituted C₂ alkylene. In embodiments, L^(1C) is substituted C₃alkylene. In embodiments, L^(1C) is substituted C₄ alkylene. Inembodiments, L^(1C) is substituted C₅ alkylene. In embodiments, L^(1C)is substituted C₆ alkylene. In embodiments, L^(1C) is substituted C₇alkylene. In embodiments, L^(1C) is substituted C₈ alkylene. Inembodiments, L^(1C) is an unsubstituted methylene. In embodiments,L^(1C) is an unsubstituted C₂ alkylene. In embodiments, L^(1C) is anunsubstituted C₃ alkylene. In embodiments, L^(1C) is an unsubstituted C₄alkylene. In embodiments, L^(1C) is an unsubstituted C₅ alkylene. Inembodiments, L^(1C) is an unsubstituted C₆ alkylene. In embodiments,L^(1C) is an unsubstituted C₇ alkylene. In embodiments, L^(1C) is anunsubstituted C₈ alkylene.

In embodiments, L^(1C) is substituted or unsubstituted C₁-C₆ alkylene.In embodiments, L^(1C) is substituted C₁-C₆ alkylene. In embodiments,L^(1C) is unsubstituted C₁-C₆ alkylene. In embodiments, L^(1C) issubstituted or unsubstituted C₂-C₆ alkylene. In embodiments, L^(1C) issubstituted C₂-C₆ alkylene. In embodiments, L^(1C) is unsubstitutedC₂-C₆ alkylene. In embodiments, L^(1C) is substituted or unsubstitutedC₁ alkylene. In embodiments, L^(1C) is substituted C₁ alkylene. Inembodiments, L^(1C) is unsubstituted C₁ alkylene. In embodiments, L^(1C)is substituted or unsubstituted C₂ alkylene. In embodiments, L^(1C) issubstituted C₂ alkylene. In embodiments, L^(1C) is unsubstituted C₂alkylene. In embodiments, L^(1C) is substituted or unsubstituted C₃alkylene. In embodiments, L^(1C) is substituted C₃ alkylene. Inembodiments, L^(1C) is unsubstituted C₃ alkylene. In embodiments, L^(1C)is substituted or unsubstituted C₄ alkylene. In embodiments, L^(1C) issubstituted C₄ alkylene. In embodiments, L^(1C) is unsubstituted C₄alkylene. In embodiments, L^(1C) is substituted or unsubstituted C₅alkylene. In embodiments, L^(1C) is substituted C₅ alkylene. Inembodiments, L^(1C) is unsubstituted C₅ alkylene. In embodiments, L^(1C)is substituted or unsubstituted C₆ alkylene. In embodiments, L^(1C) issubstituted C₆ alkylene. In embodiments, L^(1C) is unsubstituted C₆alkylene.

In embodiments, L^(1C) is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1C) is substituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1C) is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1C) is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L^(1C) is substituted 2membered heteroalkylene. In embodiments, L^(1C) is unsubstituted 2membered heteroalkylene. In embodiments, L^(1C) is substituted orunsubstituted 3 membered heteroalkylene. In embodiments, L^(1C) issubstituted 3 membered heteroalkylene. In embodiments, L^(1C) isunsubstituted 3 membered heteroalkylene. In embodiments, L^(1C) issubstituted or unsubstituted 4 membered heteroalkylene. In embodiments,L^(1C) is substituted 4 membered heteroalkylene. In embodiments, L^(1C)is unsubstituted 4 membered heteroalkylene. In embodiments, L^(1C) issubstituted or unsubstituted 5 membered heteroalkylene. In embodiments,L^(1C) is substituted 5 membered heteroalkylene. In embodiments, L^(1C)is unsubstituted 5 membered heteroalkylene. In embodiments, L^(1C) issubstituted or unsubstituted 6 membered heteroalkylene. In embodiments,L^(1C) is substituted 6 membered heteroalkylene. In embodiments, L^(1C)is unsubstituted 6 membered heteroalkylene.

In embodiments, L^(1C) is substituted or unsubstituted C₄-C₆cycloalkylene. In embodiments, L^(1C) is substituted C₄-C₆cycloalkylene. In embodiments, L^(1C) is substituted C₄-C₆cycloalkylene. In embodiments, L^(1C) is substituted or unsubstituted C₄cycloalkylene. In embodiments, L^(1C) is substituted C₄ cycloalkylene.In embodiments, L^(1C) is substituted C₄ cycloalkylene. In embodiments,L^(1C) is substituted or unsubstituted C₅ cycloalkylene. In embodiments,L^(1C) is substituted C₅ cycloalkylene. In embodiments, L^(1C) issubstituted C₅ cycloalkylene.

In embodiments, L^(1C) is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L^(1C) is substituted 5 to 6membered heterocycloalkylene. In embodiments, L^(1C) is unsubstituted 5to 6 membered heterocycloalkylene. In embodiments, L^(1C) is substitutedor unsubstituted 5 membered heterocycloalkylene. In embodiments, L^(1C)is substituted 5 membered heterocycloalkylene. In embodiments, L^(1C) isunsubstituted 5 membered heterocycloalkylene. In embodiments, L^(1C) issubstituted or unsubstituted 6 membered heterocycloalkylene. Inembodiments, L^(1C) is substituted 6 membered heterocycloalkylene. Inembodiments, L^(1C) is unsubstituted 6 membered heterocycloalkylene.

In embodiments, L^(1C) is substituted or unsubstituted phenylene. Inembodiments, L^(1C) is substituted phenylene. In embodiments, L^(1C) isunsubstituted phenylene.

In embodiments, L^(1C) is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(1C) is substituted 5 to 6 memberedheteroarylene. In embodiments, L^(1C) is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(1C) is substituted or unsubstituted 5membered heteroarylene. In embodiments, L^(1C) is substituted 5 memberedheteroarylene. In embodiments, L^(1C) is unsubstituted 5 memberedheteroarylene. In embodiments, L^(1C) is substituted or unsubstituted 6membered heteroarylene. In embodiments, L^(1C) is substituted 6 memberedheteroarylene. In embodiments, L^(1C) is unsubstituted 6 memberedheteroarylene.

In embodiments, L^(1D) is substituted or unsubstituted methylene. Inembodiments, L^(1D) is substituted or unsubstituted C₂ alkylene. Inembodiments, L^(1D) is substituted or unsubstituted C₃ alkylene. Inembodiments, L^(1D) is substituted or unsubstituted C₄ alkylene. Inembodiments, L^(1D) is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(1D) is substituted or unsubstituted C₆ alkylene. Inembodiments, L^(1D) is substituted or unsubstituted C₇ alkylene. Inembodiments, L^(1D) is substituted or unsubstituted C₈ alkylene. Inembodiments, L^(1D) is substituted methylene. In embodiments, L^(1D) issubstituted C₂ alkylene. In embodiments, L^(1D) is substituted C₃alkylene. In embodiments, L^(1D) is substituted C₄ alkylene. Inembodiments, L^(1D) is substituted C₅ alkylene. In embodiments, L^(1D)is substituted C₆ alkylene. In embodiments, L^(1D) is substituted C₇alkylene. In embodiments, L^(1D) is substituted C₈ alkylene. Inembodiments, L^(1D) is an unsubstituted methylene. In embodiments,L^(1D) is an unsubstituted C₂ alkylene. In embodiments, L^(1D) is anunsubstituted C₃ alkylene. In embodiments, L^(1D) is an unsubstituted C₄alkylene. In embodiments, L^(1D) is an unsubstituted C₅ alkylene. Inembodiments, L^(1D) is an unsubstituted C₆ alkylene. In embodiments,L^(1D) is an unsubstituted C₇ alkylene. In embodiments, L^(1D) is anunsubstituted C₈ alkylene.

In embodiments, L^(1D) is substituted or unsubstituted C₁-C₆ alkylene.In embodiments, L^(1D) is substituted C₁-C₆ alkylene. In embodiments,L^(1D) is unsubstituted C₁-C₆ alkylene. In embodiments, L^(1D) issubstituted or unsubstituted C₂-C₆ alkylene. In embodiments, L^(1D) issubstituted C₂-C₆ alkylene. In embodiments, L^(1D) is unsubstitutedC₂-C₆ alkylene. In embodiments, L^(1D) is substituted or unsubstitutedC₁ alkylene. In embodiments, L^(1D) is substituted C₁ alkylene. Inembodiments, L^(1D) is unsubstituted C₁ alkylene. In embodiments, L^(1D)is substituted or unsubstituted C₂ alkylene. In embodiments, L^(1D) issubstituted C₂ alkylene. In embodiments, L^(1D) is unsubstituted C₂alkylene. In embodiments, L^(1D) is substituted or unsubstituted C₃alkylene. In embodiments, L^(1D) is substituted C₃ alkylene. Inembodiments, L^(1D) is unsubstituted C₃ alkylene. In embodiments, L^(1D)is substituted or unsubstituted C₄ alkylene. In embodiments, L^(1D) issubstituted C₄ alkylene. In embodiments, L^(1D) is unsubstituted C₄alkylene. In embodiments, L^(1D) is substituted or unsubstituted C₅alkylene. In embodiments, L^(1D) is substituted C₅ alkylene. Inembodiments, L^(1D) is unsubstituted C₅ alkylene. In embodiments, L^(1D)is substituted or unsubstituted C₆ alkylene. In embodiments, L^(1D) issubstituted C₆ alkylene. In embodiments, L^(1D) is unsubstituted C₆alkylene.

In embodiments, L^(1D) is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1D) is substituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1D) is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1D) is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L^(1D) is substituted 2membered heteroalkylene. In embodiments, L^(1D) is unsubstituted 2membered heteroalkylene. In embodiments, L^(1D) is substituted orunsubstituted 3 membered heteroalkylene. In embodiments, L^(1D) issubstituted 3 membered heteroalkylene. In embodiments, L^(1D) isunsubstituted 3 membered heteroalkylene. In embodiments, L^(1D) issubstituted or unsubstituted 4 membered heteroalkylene. In embodiments,L^(1D) is substituted 4 membered heteroalkylene. In embodiments, L^(1D)is unsubstituted 4 membered heteroalkylene. In embodiments, L^(1D) issubstituted or unsubstituted 5 membered heteroalkylene. In embodiments,L^(1D) is substituted 5 membered heteroalkylene. In embodiments, L^(1D)is unsubstituted 5 membered heteroalkylene. In embodiments, L^(1D) issubstituted or unsubstituted 6 membered heteroalkylene. In embodiments,L^(1D) is substituted 6 membered heteroalkylene. In embodiments, L^(1D)is unsubstituted 6 membered heteroalkylene.

In embodiments, L^(1D) is substituted or unsubstituted C₄-C₆cycloalkylene. In embodiments, L^(1D) is substituted C₄-C₆cycloalkylene. In embodiments, L^(1D) is substituted C₄-C₆cycloalkylene. In embodiments, L^(1D) is substituted or unsubstituted C₄cycloalkylene. In embodiments, L^(1D) is substituted C₄ cycloalkylene.In embodiments, L^(1D) is substituted C₄ cycloalkylene. In embodiments,L^(1D) is substituted or unsubstituted C₅ cycloalkylene. In embodiments,L^(1D) is substituted C₅ cycloalkylene. In embodiments, L^(1D) issubstituted C₅ cycloalkylene.

In embodiments, L^(1D) is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L^(1D) is substituted 5 to 6membered heterocycloalkylene. In embodiments, L^(1D) is unsubstituted 5to 6 membered heterocycloalkylene. In embodiments, L^(1D) is substitutedor unsubstituted 5 membered heterocycloalkylene. In embodiments, L^(1D)is substituted 5 membered heterocycloalkylene. In embodiments, L^(1D) isunsubstituted 5 membered heterocycloalkylene. In embodiments, L^(1D) issubstituted or unsubstituted 6 membered heterocycloalkylene. Inembodiments, L^(1D) is substituted 6 membered heterocycloalkylene. Inembodiments, L^(1D) is unsubstituted 6 membered heterocycloalkylene.

In embodiments, L^(1D) is substituted or unsubstituted phenylene. Inembodiments, L^(1D) is substituted phenylene. In embodiments, L^(1D) isunsubstituted phenylene.

In embodiments, L^(1D) is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(1D) is substituted 5 to 6 memberedheteroarylene. In embodiments, L^(1D) is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(1D) is substituted or unsubstituted 5membered heteroarylene. In embodiments, L^(1D) is substituted 5 memberedheteroarylene. In embodiments, L^(1D) is unsubstituted 5 memberedheteroarylene. In embodiments, L^(1D) is substituted or unsubstituted 6membered heteroarylene. In embodiments, L^(1D) is substituted 6 memberedheteroarylene. In embodiments, L^(1D) is unsubstituted 6 memberedheteroarylene.

In embodiments, L^(1E) is substituted or unsubstituted methylene. Inembodiments, L^(1E) is substituted or unsubstituted C₂ alkylene. Inembodiments, L^(1E) is substituted or unsubstituted C₃ alkylene. Inembodiments, L^(1E) is substituted or unsubstituted C₄ alkylene. Inembodiments, L^(1E) is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(1E) is substituted or unsubstituted C₆ alkylene. Inembodiments, L^(1E) is substituted or unsubstituted C₇ alkylene. Inembodiments, L^(1E) is substituted or unsubstituted C₈ alkylene. Inembodiments, L^(1E) is substituted methylene. In embodiments, L^(1E) issubstituted C₂ alkylene. In embodiments, L^(1E) is substituted C₃alkylene. In embodiments, L^(1E) is substituted C₄ alkylene. Inembodiments, L^(1E) is substituted C₅ alkylene. In embodiments, L^(1E)is substituted C₆ alkylene. In embodiments, L^(1E) is substituted C₇alkylene. In embodiments, L^(1E) is substituted C₈ alkylene. Inembodiments, L^(1E) is an unsubstituted methylene. In embodiments,L^(1E) is an unsubstituted C₂ alkylene. In embodiments, L^(1E) is anunsubstituted C₃ alkylene. In embodiments, L^(1E) is an unsubstituted C₄alkylene. In embodiments, L^(1E) is an unsubstituted C₅ alkylene. Inembodiments, L^(1E) is an unsubstituted C₆ alkylene. In embodiments,L^(1E) is an unsubstituted C₇ alkylene. In embodiments, L^(1E) is anunsubstituted C₈ alkylene.

In embodiments, L^(1E) is substituted or unsubstituted C₁-C₆ alkylene.In embodiments, L^(1E) is substituted C₁-C₆ alkylene. In embodiments,L^(1E) is unsubstituted C₁-C₆ alkylene. In embodiments, L^(1E) issubstituted or unsubstituted C₂-C₆ alkylene. In embodiments, L^(1E) issubstituted C₂-C₆ alkylene. In embodiments, L^(1E) is unsubstitutedC₂-C₆ alkylene. In embodiments, L^(1E) is substituted or unsubstitutedC₁ alkylene. In embodiments, L^(1E) is substituted C₁ alkylene. Inembodiments, L^(1E) is unsubstituted C₁ alkylene. In embodiments, L^(1E)is substituted or unsubstituted C₂ alkylene. In embodiments, L^(1E) issubstituted C₂ alkylene. In embodiments, L^(1E) is unsubstituted C₂alkylene. In embodiments, L^(1E) is substituted or unsubstituted C₃alkylene. In embodiments, L^(1E) is substituted C₃ alkylene. Inembodiments, L^(1E) is unsubstituted C₃ alkylene. In embodiments, L^(1E)is substituted or unsubstituted C₄ alkylene. In embodiments, L^(1E) issubstituted C₄ alkylene. In embodiments, L^(1E) is unsubstituted C₄alkylene. In embodiments, L^(1E) is substituted or unsubstituted C₅alkylene. In embodiments, L^(1E) is substituted C₅ alkylene. Inembodiments, L^(1E) is unsubstituted C₅ alkylene. In embodiments, L^(1E)is substituted or unsubstituted C₆ alkylene. In embodiments, L^(1E) issubstituted C₆ alkylene. In embodiments, L^(1E) is unsubstituted C₆alkylene.

In embodiments, L^(1E) is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1E) is substituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1E) is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(1E) is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L^(1E) is substituted 2membered heteroalkylene. In embodiments, L^(1E) is unsubstituted 2membered heteroalkylene. In embodiments, L^(1E) is substituted orunsubstituted 3 membered heteroalkylene. In embodiments, L^(1E) issubstituted 3 membered heteroalkylene. In embodiments, L^(1E) isunsubstituted 3 membered heteroalkylene. In embodiments, L^(1E) issubstituted or unsubstituted 4 membered heteroalkylene. In embodiments,L^(1E) is substituted 4 membered heteroalkylene. In embodiments, L^(1E)is unsubstituted 4 membered heteroalkylene. In embodiments, L^(1E) issubstituted or unsubstituted 5 membered heteroalkylene. In embodiments,L^(1E) is substituted 5 membered heteroalkylene. In embodiments, L^(1E)is unsubstituted 5 membered heteroalkylene. In embodiments, L^(1E) issubstituted or unsubstituted 6 membered heteroalkylene. In embodiments,L^(1E) is substituted 6 membered heteroalkylene. In embodiments, L^(1E)is unsubstituted 6 membered heteroalkylene.

In embodiments, L^(1E) is substituted or unsubstituted C₄-C₆cycloalkylene. In embodiments, L^(1E) is substituted C₄-C₆cycloalkylene. In embodiments, L^(1E) is substituted C₄-C₆cycloalkylene. In embodiments, L^(1E) is substituted or unsubstituted C₄cycloalkylene. In embodiments, L^(1E) is substituted C₄ cycloalkylene.In embodiments, L^(1E) is substituted C₄ cycloalkylene. In embodiments,L^(1E) is substituted or unsubstituted C₅ cycloalkylene. In embodiments,L^(1E) is substituted C₅ cycloalkylene. In embodiments, L^(1E) issubstituted C₅ cycloalkylene.

In embodiments, L^(1E) is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L^(1E) is substituted 5 to 6membered heterocycloalkylene. In embodiments, L^(1E) is unsubstituted 5to 6 membered heterocycloalkylene. In embodiments, L^(1E) is substitutedor unsubstituted 5 membered heterocycloalkylene. In embodiments, L^(1E)is substituted 5 membered heterocycloalkylene. In embodiments, L^(1E) isunsubstituted 5 membered heterocycloalkylene. In embodiments, L^(1E) issubstituted or unsubstituted 6 membered heterocycloalkylene. Inembodiments, L^(1E) is substituted 6 membered heterocycloalkylene. Inembodiments, L^(1E) is unsubstituted 6 membered heterocycloalkylene.

In embodiments, L^(1E) is substituted or unsubstituted phenylene. Inembodiments, L^(1E) is substituted phenylene. In embodiments, L^(1E) isunsubstituted phenylene.

In embodiments, L^(1E) is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(1E) is substituted 5 to 6 memberedheteroarylene. In embodiments, L^(1E) is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(1E) is substituted or unsubstituted 5membered heteroarylene. In embodiments, L^(1E) is substituted 5 memberedheteroarylene. In embodiments, L^(1E) is unsubstituted 5 memberedheteroarylene. In embodiments, L^(1E) is substituted or unsubstituted 6membered heteroarylene. In embodiments, L^(1E) is substituted 6 memberedheteroarylene. In embodiments, L^(1E) is unsubstituted 6 memberedheteroarylene.

In embodiments, L^(1A) is a bond. In embodiments, L^(1B) is a bond. Inembodiments, L^(1C) is a bond. In embodiments, L^(1D) is a bond. Inembodiments, L^(1E) is a bond.

In embodiments, L² is L^(2A)-L^(2B)-L^(2C)-L^(2D)-L^(2E). L^(2A),L^(2B), L^(2C), L^(2D), or L^(2E) are independently a bond, —SS—, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted alkylene (e.g., alkylene, alkenylene, or alkynylene),substituted (e.g., substituted with a substituent group, size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroalkylene (e.g., heteroalkylene, heteroalkenylene, orheteroalkynylene), substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heterocycloalkylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted arylene, or substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted heteroarylene; wherein atleast one of L^(2A), L^(2B), L^(2C), L^(2D), and L^(2E) is not a bond.

In embodiments, L^(2A), L^(2B), L^(2C), L^(2D), or L^(2E) areindependently a bond, —NN—, —NHC(O)—, —C(O)NH—, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted alkylene (e.g., alkylene,alkenylene, or alkynylene), substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted heterocycloalkylene,substituted (e.g., substituted with a substituent group, size-limitedsubstituent group, or lower substituent group) or unsubstituted arylene,or substituted (e.g., substituted with a substituent group, size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroarylene; wherein at least one of L^(2A), L^(2B), L^(2C), L^(2D),and L^(2E) is not a bond.

In embodiments, L^(2A) is independently a bond, —SS—, —NN—, —NHC(O)—,—C(O)NH—, R^(52A)-substituted or unsubstituted alkylene,R^(52A)-substituted or unsubstituted heteroalkylene, R^(52A)-substitutedor unsubstituted cycloalkylene, R^(52A)-substituted or unsubstitutedheterocycloalkylene, R^(52A)-substituted or unsubstituted arylene, orR^(52A)-substituted or unsubstituted heteroarylene.

In embodiments, L^(2B) is independently a bond, —SS—, —NN—, —NHC(O)—,—C(O)NH—, R^(52B)-substituted or unsubstituted alkylene,R^(52B)-substituted or unsubstituted heteroalkylene, R^(52B)-substitutedor unsubstituted cycloalkylene, R^(52B)-substituted or unsubstitutedheterocycloalkylene, R^(52B)-substituted or unsubstituted arylene, orR^(52B)-substituted or unsubstituted heteroarylene.

In embodiments, L^(2C) is independently a bond, —SS—, —NN—, —NHC(O)—,—C(O)NH—, R^(52C)-substituted or unsubstituted alkylene,R^(52C)-substituted or unsubstituted heteroalkylene, R^(52C)-substitutedor unsubstituted cycloalkylene, R^(52C)-substituted or unsubstitutedheterocycloalkylene, R^(52C)-substituted or unsubstituted arylene, orR^(52C)-substituted or unsubstituted heteroarylene.

In embodiments, L^(2D) is independently a bond, —SS—, —NN—, —NHC(O)—,—C(O)NH—, R^(52D)-substituted or unsubstituted alkylene,R^(52D)-substituted or unsubstituted heteroalkylene, R^(52D)-substitutedor unsubstituted cycloalkylene, R^(52D)-substituted or unsubstitutedheterocycloalkylene, R^(52D)-substituted or unsubstituted arylene, orR^(52D)-substituted or unsubstituted heteroarylene.

In embodiments, L^(2E) is independently a bond, —SS—, —NN—, —NHC(O)—,—C(O)NH—, R^(52E)-substituted or unsubstituted alkylene,R^(52E)-substituted or unsubstituted heteroalkylene, R^(52E)-substitutedor unsubstituted cycloalkylene, R^(52E)-substituted or unsubstitutedheterocycloalkylene, R^(52E)-substituted or unsubstituted arylene, orR^(52E)-substituted or unsubstituted heteroarylene.

R^(52A), R^(52B), R^(52C), R^(52D), and R^(52E) are each independentlyhalogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F,—CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂,—OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, L² is L^(2A)-L^(B)-L^(2C)-L^(2D)-L^(2E); and L^(2A),L^(2B), L^(2C), L^(2D), or L^(2E) are independently a bond, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₁-C₂₀ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 20 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₂₀ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 20 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₆-C₂₀ arylene, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 20 membered heteroarylene; wherein at leastone of L^(2A), L^(2B), L^(2C), L^(2D), and L^(2E) is not a bond.

In embodiments, L² is L^(2A)-L^(2B)-L^(2C)-L^(2D)-L^(2E); and L^(2A),L^(2B), L^(2C), L^(2D), or L^(2E) are independently a bond, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₁-C₁₀ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 10 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₈ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 8 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₆-C₁₀ arylene, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 10 membered heteroarylene; wherein at leastone of L^(2A), L^(2B), L^(2C), L^(2D), and L^(2E) is not a bond.

In embodiments, L² is L^(2A)-L^(2B)-L^(2C)-L^(2D)-L^(2E); and L^(2A),L^(2B), L^(2C), L^(2D), or L^(2E) are independently a bond, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₁-C₆ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 6 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₆ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 6 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted phenyl, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 6 membered heteroarylene; wherein at leastone of L^(2A), L^(2B), L^(2C), L^(2D), and L^(2E) is not a bond.

In embodiments, L² is L^(2A)-L^(2B)-L^(2C)-L^(2D)-L^(2E); wherein L^(2A)is a bond, —NN—, —NHC(O)—, —C(O)NH—, substituted (e.g., substituted witha substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted alkylene (e.g., alkylene,alkenylene, or alkynylene), substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene); L^(2B) is a bond, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heterocycloalkylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted arylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted heteroarylene; L^(2C) is abond, —NN—, —NHC(O)—, —C(O)NH—, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted cycloalkylene, substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted arylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted heteroarylene;L^(2D) is a bond, —NN—, —NHC(O)—, —C(O)NH—, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted alkylene (e.g., alkylene,alkenylene, or alkynylene), substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene); and L^(2E) is a bond, —NN—,—NHC(O)—, —C(O)NH—, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted alkylene (e.g., alkylene, alkenylene, or alkynylene),substituted (e.g., substituted with a substituent group, size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroalkylene (e.g., heteroalkylene, heteroalkenylene, orheteroalkynylene), substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heterocycloalkylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted arylene, or substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted heteroarylene; wherein atleast one of L^(2A), L^(2B), L^(2C), L^(2D), and L^(2E) is not a bond.

In embodiments, L² is a bond, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted heteroalkylene (e.g., heteroalkylene, heteroalkenylene, orheteroalkynylene), substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted cycloalkylene, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted heterocycloalkylene, substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted arylene, or substituted (e.g.,substituted with a substituent group, size-limited substituent group, orlower substituent group) or unsubstituted heteroarylene.

In embodiments, L² is a bond, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted C₁-C₂₀ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 20 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₂₀ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 20 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₆-C₂₀ arylene, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 20 membered heteroarylene.

In embodiments, L² is a bond, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted C₁-C₈ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 8 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₈ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 8 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted C₆-C₁₀ arylene, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 10 membered heteroarylene.

In embodiments, L² is a bond, substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted C₁-C₆ alkylene (e.g., alkylene, alkenylene, oralkynylene), substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 2 to 6 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene), substituted (e.g., substitutedwith a substituent group, size-limited substituent group, or lowersubstituent group) or unsubstituted C₃-C₆ cycloalkylene, substituted(e.g., substituted with a substituent group, size-limited substituentgroup, or lower substituent group) or unsubstituted 3 to 6 memberedheterocycloalkylene, substituted (e.g., substituted with a substituentgroup, size-limited substituent group, or lower substituent group) orunsubstituted phenyl, or substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 5 to 6 membered heteroarylene.

In embodiments, L² is a substituted (e.g., substituted with asubstituent group, size-limited substituent group, or lower substituentgroup) or unsubstituted 3 to 10 membered heteroalkylene (e.g.,heteroalkylene, heteroalkenylene, or heteroalkynylene). In embodiments,L² is a substituted (e.g., substituted with a substituent group,size-limited substituent group, or lower substituent group) orunsubstituted 3 to 8 membered heteroalkylene (e.g., heteroalkylene,heteroalkenylene, or heteroalkynylene). In embodiments, L² is asubstituted (e.g., substituted with a substituent group, size-limitedsubstituent group, or lower substituent group) or unsubstituted 3 to 6membered heteroalkylene (e.g., heteroalkylene, heteroalkenylene, orheteroalkynylene).

In embodiments, L² is substituted or unsubstituted methylene. Inembodiments, L² is substituted or unsubstituted C₂ alkylene. Inembodiments, L² is substituted or unsubstituted C₃ alkylene. Inembodiments, L² is substituted or unsubstituted C₄ alkylene. Inembodiments, L² is substituted or unsubstituted C₅ alkylene. Inembodiments, L² is substituted or unsubstituted C₆ alkylene. Inembodiments, L² is substituted or unsubstituted C₇ alkylene. Inembodiments, L² is substituted or unsubstituted C₅ alkylene. Inembodiments, L² is substituted methylene. In embodiments, L² issubstituted C₂ alkylene. In embodiments, L² is substituted C₃ alkylene.In embodiments, L² is substituted C₄ alkylene. In embodiments, L² issubstituted C₅ alkylene. In embodiments, L² is substituted C₆ alkylene.In embodiments, L² is substituted C₇ alkylene. In embodiments, L² issubstituted C₅ alkylene. In embodiments, L² is an unsubstitutedmethylene. In embodiments, L² is an unsubstituted C₂ alkylene. Inembodiments, L² is an unsubstituted C₃ alkylene. In embodiments, L² isan unsubstituted C₄ alkylene. In embodiments, L² is an unsubstituted C₅alkylene. In embodiments, L² is an unsubstituted C₆ alkylene. Inembodiments, L² is an unsubstituted C₇ alkylene. In embodiments, L² isan unsubstituted C₅ alkylene.

In embodiments, L² is substituted or unsubstituted C₁-C₆ alkylene. Inembodiments, L² is substituted C₁-C₆ alkylene. In embodiments, L² isunsubstituted C₁-C₆ alkylene. In embodiments, L² is substituted orunsubstituted C₂-C₆ alkylene. In embodiments, L² is substituted C₂-C₆alkylene. In embodiments, L² is unsubstituted C₂-C₆ alkylene. Inembodiments, L² is substituted or unsubstituted C₁ alkylene. Inembodiments, L² is substituted C₁ alkylene. In embodiments, L² isunsubstituted C₁ alkylene. In embodiments, L² is substituted orunsubstituted C₂ alkylene. In embodiments, L² is substituted C₂alkylene. In embodiments, L² is unsubstituted C₂ alkylene. Inembodiments, L² is substituted or unsubstituted C₃ alkylene. Inembodiments, L² is substituted C₃ alkylene. In embodiments, L² isunsubstituted C₃ alkylene. In embodiments, L² is substituted orunsubstituted C₄ alkylene. In embodiments, L² is substituted C₄alkylene. In embodiments, L² is unsubstituted C₄ alkylene. Inembodiments, L² is substituted or unsubstituted C₅ alkylene. Inembodiments, L² is substituted C₅ alkylene. In embodiments, L² isunsubstituted C₅ alkylene. In embodiments, L² is substituted orunsubstituted C₆ alkylene. In embodiments, L² is substituted C₆alkylene. In embodiments, L² is unsubstituted C₆ alkylene.

In embodiments, L² is substituted or unsubstituted C₉ alkylene. Inembodiments, L² is substituted or unsubstituted C₁₀ alkylene. Inembodiments, L² is substituted or unsubstituted C₁₁ alkylene. Inembodiments, L² is substituted or unsubstituted C₁₂ alkylene. Inembodiments, L² is substituted or unsubstituted C₁₃ alkylene. Inembodiments, L² is substituted or unsubstituted C₁₄ alkylene. Inembodiments, L² is substituted or unsubstituted C₁₅ alkylene. Inembodiments, L² is substituted or unsubstituted C₁₆ alkylene. Inembodiments, L² is substituted or unsubstituted C₁₇ alkylene. Inembodiments, L² is substituted or unsubstituted C₁₈ alkylene. Inembodiments, L² is substituted or unsubstituted C₁₉ alkylene. Inembodiments, L² is substituted or unsubstituted C₂₀ alkylene.

In embodiments, L² is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L² is substituted 2 to 8 memberedheteroalkylene. In embodiments, L² is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L² is substituted 2 memberedheteroalkylene. In embodiments, L² is unsubstituted 2 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 3membered heteroalkylene. In embodiments, L² is substituted 3 memberedheteroalkylene. In embodiments, L² is unsubstituted 3 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 4membered heteroalkylene. In embodiments, L² is substituted 4 memberedheteroalkylene. In embodiments, L² is unsubstituted 4 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 5membered heteroalkylene. In embodiments, L² is substituted 5 memberedheteroalkylene. In embodiments, L² is unsubstituted 5 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 6membered heteroalkylene. In embodiments, L² is substituted 6 memberedheteroalkylene. In embodiments, L² is unsubstituted 6 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 7membered heteroalkylene. In embodiments, L² is substituted 7 memberedheteroalkylene. In embodiments, L² is unsubstituted 7 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 8membered heteroalkylene. In embodiments, L² is substituted 8 memberedheteroalkylene. In embodiments, L² is unsubstituted 8 memberedheteroalkylene.

In embodiments, L² is substituted or unsubstituted 9 memberedheteroalkylene. In embodiments, L² is substituted 9 memberedheteroalkylene. In embodiments, L² is unsubstituted 9 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 10membered heteroalkylene. In embodiments, L² is substituted 10 memberedheteroalkylene. In embodiments, L² is unsubstituted 10 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 11membered heteroalkylene. In embodiments, L² is substituted 11 memberedheteroalkylene. In embodiments, L² is unsubstituted 11 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 12membered heteroalkylene. In embodiments, L² is substituted 12 memberedheteroalkylene. In embodiments, L² is unsubstituted 12 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 13membered heteroalkylene. In embodiments, L² is substituted 13 memberedheteroalkylene. In embodiments, L² is unsubstituted 13 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 14membered heteroalkylene. In embodiments, L² is substituted 14 memberedheteroalkylene. In embodiments, L² is unsubstituted 14 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 15membered heteroalkylene. In embodiments, L² is substituted 15 memberedheteroalkylene. In embodiments, L² is unsubstituted 15 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 16membered heteroalkylene. In embodiments, L² is substituted 16 memberedheteroalkylene. In embodiments, L² is unsubstituted 16 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 17membered heteroalkylene. In embodiments, L² is substituted 17 memberedheteroalkylene. In embodiments, L² is unsubstituted 17 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 18membered heteroalkylene. In embodiments, L² is substituted 18 memberedheteroalkylene. In embodiments, L² is unsubstituted 18 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 19membered heteroalkylene. In embodiments, L² is substituted 19 memberedheteroalkylene. In embodiments, L² is unsubstituted 19 memberedheteroalkylene. In embodiments, L² is substituted or unsubstituted 20membered heteroalkylene. In embodiments, L² is substituted 20 memberedheteroalkylene. In embodiments, L² is unsubstituted 20 memberedheteroalkylene.

In embodiments, L² is substituted or unsubstituted C₄-C₆ cycloalkylene.In embodiments, L² is substituted C₄-C₆ cycloalkylene. In embodiments,L² is substituted C₄-C₆ cycloalkylene. In embodiments, L² is substitutedor unsubstituted C₄ cycloalkylene. In embodiments, L² is substituted C₄cycloalkylene. In embodiments, L² is substituted C₄ cycloalkylene. Inembodiments, L² is substituted or unsubstituted C₅ cycloalkylene. Inembodiments, L² is substituted C₅ cycloalkylene. In embodiments, L² issubstituted C₅ cycloalkylene.

In embodiments, L² is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L² is substituted 5 to 6 memberedheterocycloalkylene. In embodiments, L² is unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L² is substituted or unsubstituted5 membered heterocycloalkylene. In embodiments, L² is substituted 5membered heterocycloalkylene. In embodiments, L² is unsubstituted 5membered heterocycloalkylene. In embodiments, L² is substituted orunsubstituted 6 membered heterocycloalkylene. In embodiments, L² issubstituted 6 membered heterocycloalkylene. In embodiments, L² isunsubstituted 6 membered heterocycloalkylene.

In embodiments, L² is substituted or unsubstituted phenylene. Inembodiments, L² is substituted phenylene. In embodiments, L² isunsubstituted phenylene.

In embodiments, L² is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L² is substituted 5 to 6 memberedheteroarylene. In embodiments, L² is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L² is substituted or unsubstituted 5membered heteroarylene. In embodiments, L² is substituted 5 memberedheteroarylene. In embodiments, L² is unsubstituted 5 memberedheteroarylene. In embodiments, L² is substituted or unsubstituted 6membered heteroarylene. In embodiments, L² is substituted 6 memberedheteroarylene. In embodiments, L² is unsubstituted 6 memberedheteroarylene.

In embodiments, L² is a polymer.

In embodiments, L^(2A) is substituted or unsubstituted methylene. Inembodiments, L^(2A) is substituted or unsubstituted C₂ alkylene. Inembodiments, L^(2A) is substituted or unsubstituted C₃ alkylene. Inembodiments, L^(2A) is substituted or unsubstituted C₄ alkylene. Inembodiments, L^(2A) is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(2A) is substituted or unsubstituted C₆ alkylene. Inembodiments, L^(2A) is substituted or unsubstituted C₇ alkylene. Inembodiments, L^(2A) is substituted or unsubstituted C₈ alkylene. Inembodiments, L^(2A) is substituted methylene. In embodiments, L^(2A) issubstituted C₂ alkylene. In embodiments, L^(2A) is substituted C₃alkylene. In embodiments, L^(2A) is substituted C₄ alkylene. Inembodiments, L^(2A) is substituted C₅ alkylene. In embodiments, L^(2A)is substituted C₆ alkylene. In embodiments, L^(2A) is substituted C₇alkylene. In embodiments, L^(2A) is substituted C₈ alkylene. Inembodiments, L^(2A) is an unsubstituted methylene. In embodiments,L^(2A) is an unsubstituted C₂ alkylene. In embodiments, L^(2A) is anunsubstituted C₃ alkylene. In embodiments, L^(2A) is an unsubstituted C₄alkylene. In embodiments, L^(2A) is an unsubstituted C₅ alkylene. Inembodiments, L^(2A) is an unsubstituted C₆ alkylene. In embodiments,L^(2A) is an unsubstituted C₇ alkylene. In embodiments, L^(2A) is anunsubstituted C₈ alkylene.

In embodiments, L^(2A) is substituted or unsubstituted C₁-C₆ alkylene.In embodiments, L^(2A) is substituted C₁-C₆ alkylene. In embodiments,L^(2A) is unsubstituted C₁-C₆ alkylene. In embodiments, L^(2A) issubstituted or unsubstituted C₂₋₆ alkylene. In embodiments, L^(2A) issubstituted C₂-C₆ alkylene. In embodiments, L^(2A) is unsubstitutedC₂-C₆ alkylene. In embodiments, L^(2A) is substituted or unsubstitutedC₁ alkylene. In embodiments, L^(2A) is substituted C₁ alkylene. Inembodiments, L^(2A) is unsubstituted C₁ alkylene. In embodiments, L^(2A)is substituted or unsubstituted C₂ alkylene. In embodiments, L^(2A) issubstituted C₂ alkylene. In embodiments, L^(2A) is unsubstituted C₂alkylene. In embodiments, L^(2A) is substituted or unsubstituted C₃alkylene. In embodiments, L^(2A) is substituted C₃ alkylene. Inembodiments, L^(2A) is unsubstituted C₃ alkylene. In embodiments, L^(2A)is substituted or unsubstituted C₄ alkylene. In embodiments, L^(2A) issubstituted C₄ alkylene. In embodiments, L^(2A) is unsubstituted C₄alkylene. In embodiments, L^(2A) is substituted or unsubstituted C₅alkylene. In embodiments, L^(2A) is substituted C₅ alkylene. Inembodiments, L^(2A) is unsubstituted C₅ alkylene. In embodiments, L^(2A)is substituted or unsubstituted C₆ alkylene. In embodiments, L^(2A) issubstituted C₆ alkylene. In embodiments, L^(2A) is unsubstituted C₆alkylene.

In embodiments, L^(2A) is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2A) is substituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2A) is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2A) is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L^(2A) is substituted 2membered heteroalkylene. In embodiments, L^(2A) is unsubstituted 2membered heteroalkylene. In embodiments, L^(2A) is substituted orunsubstituted 3 membered heteroalkylene. In embodiments, L^(2A) issubstituted 3 membered heteroalkylene. In embodiments, L^(2A) isunsubstituted 3 membered heteroalkylene. In embodiments, L^(2A) issubstituted or unsubstituted 4 membered heteroalkylene. In embodiments,L^(2A) is substituted 4 membered heteroalkylene. In embodiments, L^(2A)is unsubstituted 4 membered heteroalkylene. In embodiments, L^(2A) issubstituted or unsubstituted 5 membered heteroalkylene. In embodiments,L^(2A) is substituted 5 membered heteroalkylene. In embodiments, L^(2A)is unsubstituted 5 membered heteroalkylene. In embodiments, L^(2A) issubstituted or unsubstituted 6 membered heteroalkylene. In embodiments,L^(2A) is substituted 6 membered heteroalkylene. In embodiments, L^(2A)is unsubstituted 6 membered heteroalkylene.

In embodiments, L^(2A) is substituted or unsubstituted C₄-C₆cycloalkylene. In embodiments, L^(2A) is substituted C₄-C₆cycloalkylene. In embodiments, L^(2A) is substituted C₄-C₆cycloalkylene. In embodiments, L^(2A) is substituted or unsubstituted C₄cycloalkylene. In embodiments, L^(2A) is substituted C₄ cycloalkylene.In embodiments, L^(2A) is substituted C₄ cycloalkylene. In embodiments,L^(2A) is substituted or unsubstituted C₅ cycloalkylene. In embodiments,L^(2A) is substituted C₅ cycloalkylene. In embodiments, L^(2A) issubstituted C₅ cycloalkylene.

In embodiments, L^(2A) is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L^(2A) is substituted 5 to 6membered heterocycloalkylene. In embodiments, L^(2A) is unsubstituted 5to 6 membered heterocycloalkylene. In embodiments, L^(2A) is substitutedor unsubstituted 5 membered heterocycloalkylene. In embodiments, L^(2A)is substituted 5 membered heterocycloalkylene. In embodiments, L^(2A) isunsubstituted 5 membered heterocycloalkylene. In embodiments, L^(2A) issubstituted or unsubstituted 6 membered heterocycloalkylene. Inembodiments, L^(2A) is substituted 6 membered heterocycloalkylene. Inembodiments, L^(2A) is unsubstituted 6 membered heterocycloalkylene.

In embodiments, L^(2A) is substituted or unsubstituted phenylene. Inembodiments, L^(2A) is substituted phenylene. In embodiments, L^(2A) isunsubstituted phenylene.

In embodiments, L^(2A) is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(2A) is substituted 5 to 6 memberedheteroarylene. In embodiments, L^(2A) is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(2A) is substituted or unsubstituted 5membered heteroarylene. In embodiments, L^(2A) is substituted 5 memberedheteroarylene. In embodiments, L^(2A) is unsubstituted 5 memberedheteroarylene. In embodiments, L^(2A) is substituted or unsubstituted 6membered heteroarylene. In embodiments, L^(2A) is substituted 6 memberedheteroarylene. In embodiments, L^(2A) is unsubstituted 6 memberedheteroarylene.

In embodiments, L^(2A) is a polymer.

In embodiments, L^(2B) is substituted or unsubstituted methylene. Inembodiments, L^(2B) is substituted or unsubstituted C₂ alkylene. Inembodiments, L^(2B) is substituted or unsubstituted C₃ alkylene. Inembodiments, L^(2B) is substituted or unsubstituted C₄ alkylene. Inembodiments, L^(2B) is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(2B) is substituted or unsubstituted C₆ alkylene. Inembodiments, L^(2B) is substituted or unsubstituted C₇ alkylene. Inembodiments, L^(2B) is substituted or unsubstituted C₈ alkylene. Inembodiments, L^(2B) is substituted methylene. In embodiments, L^(2B) issubstituted C₂ alkylene. In embodiments, L^(2B) is substituted C₃alkylene. In embodiments, L^(2B) is substituted C₄ alkylene. Inembodiments, L^(2B) is substituted C₅ alkylene. In embodiments, L^(2B)is substituted C₆ alkylene. In embodiments, L^(2B) is substituted C₇alkylene. In embodiments, L^(2B) is substituted C₈ alkylene. Inembodiments, L^(2B) is an unsubstituted methylene. In embodiments,L^(2B) is an unsubstituted C₂ alkylene. In embodiments L^(2B) is anunsubstituted C₃ alkylene. In embodiments, L^(2B) is an unsubstituted C₄alkylene. In embodiments, L^(2B) is an unsubstituted C₅ alkylene. Inembodiments, L^(2B) is an unsubstituted C₆ alkylene. In embodiments,L^(2B) is an unsubstituted C₇ alkylene. In embodiments, L^(2B) is anunsubstituted C₈ alkylene.

In embodiments, L^(2B) is substituted or unsubstituted C₁-C₆ alkylene.In embodiments, L^(2B) is substituted C₁-C₆ alkylene. In embodiments,L^(2B) is unsubstituted C₁-C₆ alkylene. In embodiments, L^(2B) issubstituted or unsubstituted C₂-C₆ alkylene. In embodiments, L^(2B) issubstituted C₂-C₆ alkylene. In embodiments, L^(2B) is unsubstitutedC₂-C₆ alkylene. In embodiments, L^(2B) is substituted or unsubstitutedC₁ alkylene. In embodiments, L^(2B) is substituted C₁ alkylene. Inembodiments, L^(2B) is unsubstituted C₁ alkylene. In embodiments, L^(2B)is substituted or unsubstituted C₂ alkylene. In embodiments, L^(2B) issubstituted C₂ alkylene. In embodiments, L^(2B) is unsubstituted C₂alkylene. In embodiments, L^(2B) is substituted or unsubstituted C₃alkylene. In embodiments, L^(2B) is substituted C₃ alkylene. Inembodiments, L^(2B) is unsubstituted C₃ alkylene. In embodiments, L^(2B)is substituted or unsubstituted C₄ alkylene. In embodiments, L^(2B) issubstituted C₄ alkylene. In embodiments, L^(2B) is unsubstituted C₄alkylene. In embodiments, L^(2B) is substituted or unsubstituted C₅alkylene. In embodiments, L^(2B) is substituted C₅ alkylene. Inembodiments, L^(2B) is unsubstituted C₅ alkylene. In embodiments, L^(2B)is substituted or unsubstituted C₆ alkylene. In embodiments, L^(2B) issubstituted C₆ alkylene. In embodiments, L^(2B) is unsubstituted C₆alkylene.

In embodiments, L^(2B) is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2B) is substituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2B) is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2B) is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L^(2B) is substituted 2membered heteroalkylene. In embodiments, L^(2B) is unsubstituted 2membered heteroalkylene. In embodiments, L^(2B) is substituted orunsubstituted 3 membered heteroalkylene. In embodiments, L^(2B) issubstituted 3 membered heteroalkylene. In embodiments, L^(2B) isunsubstituted 3 membered heteroalkylene. In embodiments, L^(2B) issubstituted or unsubstituted 4 membered heteroalkylene. In embodiments,L^(2B) is substituted 4 membered heteroalkylene. In embodiments, L^(2B)is unsubstituted 4 membered heteroalkylene. In embodiments, L^(2B) issubstituted or unsubstituted 5 membered heteroalkylene. In embodiments,L^(2B) is substituted 5 membered heteroalkylene. In embodiments, L^(2B)is unsubstituted 5 membered heteroalkylene. In embodiments, L^(2B) issubstituted or unsubstituted 6 membered heteroalkylene. In embodiments,L^(2B) is substituted 6 membered heteroalkylene. In embodiments, L^(2B)is unsubstituted 6 membered heteroalkylene.

In embodiments, L^(2B) is substituted or unsubstituted C₄-C₆cycloalkylene. In embodiments, L^(2B) is substituted C₄-C₆cycloalkylene. In embodiments, L^(2B) is substituted C₄-C₆cycloalkylene. In embodiments, L^(2B) is substituted or unsubstituted C₄cycloalkylene. In embodiments, L^(2B) is substituted C₄ cycloalkylene.In embodiments, L^(2B) is substituted C₄ cycloalkylene. In embodiments,L^(2B) is substituted or unsubstituted C₅ cycloalkylene. In embodiments,L^(2B) is substituted C₅ cycloalkylene. In embodiments, L^(2B) issubstituted C₅ cycloalkylene.

In embodiments, L^(2B) is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L^(2B) is substituted 5 to 6membered heterocycloalkylene. In embodiments, L^(2B) is unsubstituted 5to 6 membered heterocycloalkylene. In embodiments, L^(2B) is substitutedor unsubstituted 5 membered heterocycloalkylene. In embodiments, L^(2B)is substituted 5 membered heterocycloalkylene. In embodiments, L^(2B) isunsubstituted 5 membered heterocycloalkylene. In embodiments, L^(2B) issubstituted or unsubstituted 6 membered heterocycloalkylene. Inembodiments, L^(2B) is substituted 6 membered heterocycloalkylene. Inembodiments, L^(2B) is unsubstituted 6 membered heterocycloalkylene.

In embodiments, L^(2B) is substituted or unsubstituted phenylene. Inembodiments, L^(2B) is substituted phenylene. In embodiments, L^(2B) isunsubstituted phenylene.

In embodiments, L^(2B) is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(2B) is substituted 5 to 6 memberedheteroarylene. In embodiments, L^(2B) is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(2B) is substituted or unsubstituted 5membered heteroarylene. In embodiments, L^(2B) is substituted 5 memberedheteroarylene. In embodiments, L^(2B) is unsubstituted 5 memberedheteroarylene. In embodiments, L^(2B) is substituted or unsubstituted 6membered heteroarylene. In embodiments, L^(2B) is substituted 6 memberedheteroarylene. In embodiments, L^(2B) is unsubstituted 6 memberedheteroarylene.

In embodiments, L^(2C) is substituted or unsubstituted methylene. Inembodiments, L^(2C) is substituted or unsubstituted C₂ alkylene. Inembodiments, L^(2C) is substituted or unsubstituted C₃ alkylene. Inembodiments, L^(2C) is substituted or unsubstituted C₄ alkylene. Inembodiments, L^(2C) is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(2C) is substituted or unsubstituted C₆ alkylene. Inembodiments, L^(2C) is substituted or unsubstituted C₇ alkylene. Inembodiments, LC is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(2C) is substituted methylene. In embodiments, L^(2C) issubstituted C₂ alkylene. In embodiments, L^(2C) is substituted C₃alkylene. In embodiments, L^(2C) is substituted C₄ alkylene. Inembodiments, L^(2C) is substituted C₅ alkylene. In embodiments, L^(2C)is substituted C₆ alkylene. In embodiments, L^(2C) is substituted C₇alkylene. In embodiments, L^(2C) is substituted C₈ alkylene. Inembodiments, L^(2C) is an unsubstituted methylene. In embodiments,L^(2C) is an unsubstituted C₂ alkylene. In embodiments, L^(2C) is anunsubstituted C₃ alkylene. In embodiments, L^(2C) is an unsubstituted C₄alkylene. In embodiments, L^(2C) is an unsubstituted C₅ alkylene. Inembodiments, L^(2C) is an unsubstituted C₆ alkylene. In embodiments,L^(2C) is an unsubstituted C₇ alkylene. In embodiments, L^(2C) is anunsubstituted C₅ alkylene.

In embodiments, L^(2C) is substituted or unsubstituted C₁-C₆ alkylene.In embodiments, L^(2C) is substituted C₁-C₆ alkylene. In embodiments,L^(2C) is unsubstituted C₁-C₆ alkylene. In embodiments, L^(2C) issubstituted or unsubstituted C₂-C₆ alkylene. In embodiments, L^(2C) issubstituted C₂-C₆ alkylene. In embodiments, L^(2C) is unsubstitutedC₂-C₆ alkylene. In embodiments, L^(2C) is substituted or unsubstitutedC₁ alkylene. In embodiments, L^(2C) is substituted C₁ alkylene. Inembodiments, L^(2C) is unsubstituted C₁ alkylene. In embodiments, L^(2C)is substituted or unsubstituted C₂ alkylene. In embodiments, L^(2C) issubstituted C₂ alkylene. In embodiments, L^(2C) is unsubstituted C₂alkylene. In embodiments, L^(2C) is substituted or unsubstituted C₃alkylene. In embodiments, L^(2C) is substituted C₃ alkylene. Inembodiments, L^(2C) is unsubstituted C₃ alkylene. In embodiments, L^(2C)is substituted or unsubstituted C₄ alkylene. In embodiments, L^(2C) issubstituted C₄ alkylene. In embodiments, L^(2C) is unsubstituted C₄alkylene. In embodiments, L^(2C) is substituted or unsubstituted C₅alkylene. In embodiments, L^(2C) is substituted C₅ alkylene. Inembodiments, L^(2C) is unsubstituted C₅ alkylene. In embodiments, L^(2C)is substituted or unsubstituted C₆ alkylene. In embodiments, L^(2C) issubstituted C₆ alkylene. In embodiments, L^(2C) is unsubstituted C₆alkylene.

In embodiments, L^(2C) is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2C) is substituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2C) is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2C) is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L^(2C) is substituted 2membered heteroalkylene. In embodiments, L^(2C) is unsubstituted 2membered heteroalkylene. In embodiments, L^(2C) is substituted orunsubstituted 3 membered heteroalkylene. In embodiments, L^(2C) issubstituted 3 membered heteroalkylene. In embodiments, L^(2C) isunsubstituted 3 membered heteroalkylene. In embodiments, L^(2C) issubstituted or unsubstituted 4 membered heteroalkylene. In embodiments,L^(2C) is substituted 4 membered heteroalkylene. In embodiments, L^(2C)is unsubstituted 4 membered heteroalkylene. In embodiments, L^(2C) issubstituted or unsubstituted 5 membered heteroalkylene. In embodiments,L^(2C) is substituted 5 membered heteroalkylene. In embodiments, L^(2C)is unsubstituted 5 membered heteroalkylene. In embodiments, L^(2C) issubstituted or unsubstituted 6 membered heteroalkylene. In embodiments,L^(2C) is substituted 6 membered heteroalkylene. In embodiments, L^(2C)is unsubstituted 6 membered heteroalkylene.

In embodiments, L^(2C) is substituted or unsubstituted C₄-C₆cycloalkylene. In embodiments, L^(2C) is substituted C₄-C₆cycloalkylene. In embodiments, L^(2C) is substituted C₄-C₆cycloalkylene. In embodiments, L^(2C) is substituted or unsubstituted C₄cycloalkylene. In embodiments, L^(2C) is substituted C₄ cycloalkylene.In embodiments, L^(2C) is substituted C₄ cycloalkylene. In embodiments,L^(2C) is substituted or unsubstituted C₅ cycloalkylene. In embodiments,L^(2C) is substituted C₅ cycloalkylene. In embodiments, L^(2C) issubstituted C₅ cycloalkylene.

In embodiments, L^(2C) is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L^(2C) is substituted 5 to 6membered heterocycloalkylene. In embodiments, L^(2C) is unsubstituted 5to 6 membered heterocycloalkylene. In embodiments, L^(2C) is substitutedor unsubstituted 5 membered heterocycloalkylene. In embodiments, L^(2C)is substituted 5 membered heterocycloalkylene. In embodiments, L^(2C) isunsubstituted 5 membered heterocycloalkylene. In embodiments, L^(2C) issubstituted or unsubstituted 6 membered heterocycloalkylene. Inembodiments, L^(2C) is substituted 6 membered heterocycloalkylene. Inembodiments, L^(2C) is unsubstituted 6 membered heterocycloalkylene.

In embodiments, L^(2C) is substituted or unsubstituted phenylene. Inembodiments, L^(2C) is substituted phenylene. In embodiments, L^(2C) isunsubstituted phenylene.

In embodiments, L^(2C) is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(2C) is substituted 5 to 6 memberedheteroarylene. In embodiments, L^(2C) is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(2C) is substituted or unsubstituted 5membered heteroarylene. In embodiments, L^(2C) is substituted 5 memberedheteroarylene. In embodiments, L^(2C) is unsubstituted 5 memberedheteroarylene. In embodiments, L^(2C) is substituted or unsubstituted 6membered heteroarylene. In embodiments, L^(2C) is substituted 6 memberedheteroarylene. In embodiments, L^(2C) is unsubstituted 6 memberedheteroarylene.

In embodiments, L^(2D) is substituted or unsubstituted methylene. Inembodiments, L^(2D) is substituted or unsubstituted C₂ alkylene. Inembodiments, L^(2D) is substituted or unsubstituted C₃ alkylene. Inembodiments, L^(2D) is substituted or unsubstituted C₄ alkylene. Inembodiments, L^(2D) is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(2D) is substituted or unsubstituted C₆ alkylene. Inembodiments, L^(2D) is substituted or unsubstituted C₇ alkylene. Inembodiments, L^(2D) is substituted or unsubstituted C₈ alkylene. Inembodiments, L^(2D) is substituted methylene. In embodiments, L^(2D) issubstituted C₂ alkylene. In embodiments, L^(2D) is substituted C₃alkylene. In embodiments, L^(2D) is substituted C₄ alkylene. Inembodiments, L^(2D) is substituted C₅ alkylene. In embodiments, L^(2D)is substituted C₆ alkylene. In embodiments, L^(2D) is substituted C₇alkylene. In embodiments, L^(2D) is substituted C₈ alkylene. Inembodiments, L^(2D) is an unsubstituted methylene. In embodiments,L^(2D) is an unsubstituted C₂ alkylene. In embodiments L^(2D) is anunsubstituted C₃ alkylene. In embodiments, L^(2D) is an unsubstituted C₄alkylene. In embodiments, L^(2D) is an unsubstituted C₅ alkylene. Inembodiments, L^(2D) is an unsubstituted C₆ alkylene. In embodiments,L^(2D) is an unsubstituted C₇ alkylene. In embodiments, L^(2D) is anunsubstituted C₈ alkylene.

In embodiments, L^(2D) is substituted or unsubstituted C₁-C₆ alkylene.In embodiments, L^(2D) is substituted C₁-C₆ alkylene. In embodiments,L^(2D) is unsubstituted C₁-C₆ alkylene. In embodiments, L^(2D) issubstituted or unsubstituted C₂-C₆ alkylene. In embodiments, L^(2D) issubstituted C₂-C₆ alkylene. In embodiments, L^(2D) is unsubstitutedC₂-C₆ alkylene. In embodiments, L^(2D) is substituted or unsubstitutedC₁ alkylene. In embodiments, L^(2D) is substituted C₁ alkylene. Inembodiments, L^(2D) is unsubstituted C₁ alkylene. In embodiments, L^(2D)is substituted or unsubstituted C₂ alkylene. In embodiments, L^(2D) issubstituted C₂ alkylene. In embodiments, L^(2D) is unsubstituted C₂alkylene. In embodiments, L^(2D) is substituted or unsubstituted C₃alkylene. In embodiments, L^(2D) is substituted C₃ alkylene. Inembodiments, L^(2D) is unsubstituted C₃ alkylene. In embodiments, L^(2D)is substituted or unsubstituted C₄ alkylene. In embodiments, L^(2D) issubstituted C₄ alkylene. In embodiments, L^(2D) is unsubstituted C₄alkylene. In embodiments, L^(2D) is substituted or unsubstituted C₅alkylene. In embodiments, L^(2D) is substituted C₅ alkylene. Inembodiments, L^(2D) is unsubstituted C₅ alkylene. In embodiments, L^(2D)is substituted or unsubstituted C₆ alkylene. In embodiments, L^(2D) issubstituted C₆ alkylene. In embodiments, L^(2D) is unsubstituted C₆alkylene.

In embodiments, L^(2D) is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2D) is substituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2D) is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2D) is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L^(2D) is substituted 2membered heteroalkylene. In embodiments, L^(2D) is unsubstituted 2membered heteroalkylene. In embodiments, L^(2D) is substituted orunsubstituted 3 membered heteroalkylene. In embodiments, L^(2D) issubstituted 3 membered heteroalkylene. In embodiments, L^(2D) isunsubstituted 3 membered heteroalkylene. In embodiments, L^(2D) issubstituted or unsubstituted 4 membered heteroalkylene. In embodiments,L^(2D) is substituted 4 membered heteroalkylene. In embodiments, L^(2D)is unsubstituted 4 membered heteroalkylene. In embodiments, L^(2D) issubstituted or unsubstituted 5 membered heteroalkylene. In embodiments,L^(2D) is substituted 5 membered heteroalkylene. In embodiments, L^(2D)is unsubstituted 5 membered heteroalkylene. In embodiments, L^(2D) issubstituted or unsubstituted 6 membered heteroalkylene. In embodiments,L^(2D) is substituted 6 membered heteroalkylene. In embodiments, L^(2D)is unsubstituted 6 membered heteroalkylene.

In embodiments, L^(2D) is substituted or unsubstituted C₄-C₆cycloalkylene. In embodiments, L^(2D) is substituted C₄-C₆cycloalkylene. In embodiments, L^(2D) is substituted C₄-C₆cycloalkylene. In embodiments, L^(2D) is substituted or unsubstituted C₄cycloalkylene. In embodiments, L^(2D) is substituted C₄ cycloalkylene.In embodiments, L^(2D) is substituted C₄ cycloalkylene. In embodiments,L^(2D) is substituted or unsubstituted C₅ cycloalkylene. In embodiments,L^(2D) is substituted C₅ cycloalkylene. In embodiments, L^(2D) issubstituted C₅ cycloalkylene.

In embodiments, L^(2D) is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L^(2D) is substituted 5 to 6membered heterocycloalkylene. In embodiments, L^(2D) is unsubstituted 5to 6 membered heterocycloalkylene. In embodiments, L^(2D) is substitutedor unsubstituted 5 membered heterocycloalkylene. In embodiments, L^(2D)is substituted 5 membered heterocycloalkylene. In embodiments, L^(2D) isunsubstituted 5 membered heterocycloalkylene. In embodiments, L^(2D) issubstituted or unsubstituted 6 membered heterocycloalkylene. Inembodiments, L^(2D) is substituted 6 membered heterocycloalkylene. Inembodiments, L^(2D) is unsubstituted 6 membered heterocycloalkylene.

In embodiments, L^(2D) is substituted or unsubstituted phenylene. Inembodiments, L^(2D) is substituted phenylene. In embodiments, L^(2D) isunsubstituted phenylene.

In embodiments, L^(2D) is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(2D) is substituted 5 to 6 memberedheteroarylene. In embodiments, L^(2D) is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(2D) is substituted or unsubstituted 5membered heteroarylene. In embodiments, L^(2D) is substituted 5 memberedheteroarylene. In embodiments, L^(2D) is unsubstituted 5 memberedheteroarylene. In embodiments, L^(2D) is substituted or unsubstituted 6membered heteroarylene. In embodiments, L^(2D) is substituted 6 memberedheteroarylene. In embodiments, L^(2D) is unsubstituted 6 memberedheteroarylene.

In embodiments, L^(2E) is substituted or unsubstituted methylene. Inembodiments, L^(2E) is substituted or unsubstituted C₂ alkylene. Inembodiments, L^(2E) is substituted or unsubstituted C₃ alkylene. Inembodiments, L^(2E) is substituted or unsubstituted C₄ alkylene. Inembodiments, L^(2E) is substituted or unsubstituted C₅ alkylene. Inembodiments, L^(2E) is substituted or unsubstituted C₆ alkylene. Inembodiments, L^(2E) is substituted or unsubstituted C₇ alkylene. Inembodiments, L^(2E) is substituted or unsubstituted C₈ alkylene. Inembodiments, L^(2E) is substituted methylene. In embodiments, L^(2E) issubstituted C₂ alkylene. In embodiments, L^(2E) is substituted C₃alkylene. In embodiments, L^(2E) is substituted C₄ alkylene. Inembodiments, L^(2E) is substituted C₅ alkylene. In embodiments, L^(2E)is substituted C₆ alkylene. In embodiments, L^(2E) is substituted C₇alkylene. In embodiments, L^(2E) is substituted C₈ alkylene. Inembodiments, L^(2E) is an unsubstituted methylene. In embodiments,L^(2E) is an unsubstituted C₂ alkylene. In embodiments, L^(2E) is anunsubstituted C₃ alkylene. In embodiments, L^(2E) is an unsubstituted C₄alkylene. In embodiments, L^(2E) is an unsubstituted C₅ alkylene. Inembodiments, L^(2E) is an unsubstituted C₆ alkylene. In embodiments,L^(2E) is an unsubstituted C₇ alkylene. In embodiments, L^(2E) is anunsubstituted C₈ alkylene.

In embodiments, L^(2E) is substituted or unsubstituted C₁-C₆ alkylene.In embodiments, L^(2E) is substituted C₁-C₆ alkylene. In embodiments,L^(2E) is unsubstituted C₁-C₆ alkylene. In embodiments, L^(2E) issubstituted or unsubstituted C₂-C₆ alkylene. In embodiments, L^(2E) issubstituted C₂-C₆ alkylene. In embodiments, L^(2E) is unsubstitutedC₂-C₆ alkylene. In embodiments, L^(2E) is substituted or unsubstitutedC₁ alkylene. In embodiments, L^(2E) is substituted C₁ alkylene. Inembodiments, L^(2E) is unsubstituted C₁ alkylene. In embodiments, L^(2E)is substituted or unsubstituted C₂ alkylene. In embodiments, L^(2E) issubstituted C₂ alkylene. In embodiments, L^(2E) is unsubstituted C₂alkylene. In embodiments, L^(2E) is substituted or unsubstituted C₃alkylene. In embodiments, L^(2E) is substituted C₃ alkylene. Inembodiments, L^(2E) is unsubstituted C₃ alkylene. In embodiments, L^(2E)is substituted or unsubstituted C₄ alkylene. In embodiments, L^(2E) issubstituted C₄ alkylene. In embodiments, L^(2E) is unsubstituted C₄alkylene. In embodiments, L^(2E) is substituted or unsubstituted C₅alkylene. In embodiments, L^(2E) is substituted C₅ alkylene. Inembodiments, L^(2E) is unsubstituted C₅ alkylene. In embodiments, L^(2E)is substituted or unsubstituted C₆ alkylene. In embodiments, L^(2E) issubstituted C₆ alkylene. In embodiments, L^(2E) is unsubstituted C₆alkylene.

In embodiments, L^(2E) is substituted or unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2E) is substituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2E) is unsubstituted 2 to 8 memberedheteroalkylene. In embodiments, L^(2E) is substituted or unsubstituted 2membered heteroalkylene. In embodiments, L^(2E) is substituted 2membered heteroalkylene. In embodiments, L^(2E) is unsubstituted 2membered heteroalkylene. In embodiments, L^(2E) is substituted orunsubstituted 3 membered heteroalkylene. In embodiments, L^(2E) issubstituted 3 membered heteroalkylene. In embodiments, L^(2E) isunsubstituted 3 membered heteroalkylene. In embodiments, L^(2E) issubstituted or unsubstituted 4 membered heteroalkylene. In embodiments,L^(2E) is substituted 4 membered heteroalkylene. In embodiments, L^(2E)is unsubstituted 4 membered heteroalkylene. In embodiments, L^(2E) issubstituted or unsubstituted 5 membered heteroalkylene. In embodiments,L^(2E) is substituted 5 membered heteroalkylene. In embodiments, L^(2E)is unsubstituted 5 membered heteroalkylene. In embodiments, L^(2E) issubstituted or unsubstituted 6 membered heteroalkylene. In embodiments,L^(2E) is substituted 6 membered heteroalkylene. In embodiments, L^(2E)is unsubstituted 6 membered heteroalkylene.

In embodiments, L^(2E) is substituted or unsubstituted C₄-C₆cycloalkylene. In embodiments, L^(2E) is substituted C₄-C₆cycloalkylene. In embodiments, L^(2E) is substituted C₄-C₆cycloalkylene. In embodiments, L^(2E) is substituted or unsubstituted C₄cycloalkylene. In embodiments, L^(2E) is substituted C₄ cycloalkylene.In embodiments, L^(2E) is substituted C₄ cycloalkylene. In embodiments,L^(2E) is substituted or unsubstituted C₅ cycloalkylene. In embodiments,L^(2E) is substituted C₅ cycloalkylene. In embodiments, L^(2E) issubstituted C₅ cycloalkylene.

In embodiments, L^(2E) is substituted or unsubstituted 5 to 6 memberedheterocycloalkylene. In embodiments, L^(2E) is substituted 5 to 6membered heterocycloalkylene. In embodiments, L^(2E) is unsubstituted 5to 6 membered heterocycloalkylene. In embodiments, L^(2E) is substitutedor unsubstituted 5 membered heterocycloalkylene. In embodiments, L^(2E)is substituted 5 membered heterocycloalkylene. In embodiments, L^(2E) isunsubstituted 5 membered heterocycloalkylene. In embodiments, L^(2E) issubstituted or unsubstituted 6 membered heterocycloalkylene. Inembodiments, L^(2E) is substituted 6 membered heterocycloalkylene. Inembodiments, L^(2E) is unsubstituted 6 membered heterocycloalkylene.

In embodiments, L^(2E) is substituted or unsubstituted phenylene. Inembodiments, L^(2E) is substituted phenylene. In embodiments, L^(2E) isunsubstituted phenylene.

In embodiments, L^(2E) is substituted or unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(2E) is substituted 5 to 6 memberedheteroarylene. In embodiments, L^(2E) is unsubstituted 5 to 6 memberedheteroarylene. In embodiments, L^(2E) is substituted or unsubstituted 5membered heteroarylene. In embodiments, L^(2E) is substituted 5 memberedheteroarylene. In embodiments, L^(2E) is unsubstituted 5 memberedheteroarylene. In embodiments, L^(2E) is substituted or unsubstituted 6membered heteroarylene. In embodiments, L^(2E) is substituted 6 memberedheteroarylene. In embodiments, L^(2E) is unsubstituted 6 memberedheteroarylene.

In embodiments, L^(2A) is a bond. In embodiments, L^(2B) is a bond. Inembodiments, L^(2C) is a bond. In embodiments, L^(2D) is a bond. Inembodiments, L^(2E) is a bond.

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D is)

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is a bond. In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is a bond.

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(1A) is

L^(1B) is

L^(1C) is

L^(1D) is

and L^(1E) is

In embodiments, L^(1A) is

In embodiments, L^(1B) is

In embodiments, L^(1C) is

In embodiments, L^(1D) is

In embodiments, L^(1E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is a bond. In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is a bond.

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, L^(2A) is

L^(2B) is

L^(2C) is

L^(2D) is

and L^(2E) is

In embodiments, L^(2A) is

In embodiments, L^(2B) is

In embodiments, L^(2C) is

In embodiments, L^(2D) is

In embodiments, L^(2E) is

In embodiments, R¹ is substituted or unsubstituted C₁-C₆ alkyl. Inembodiments, R¹ is substituted or unsubstituted C₁-C₃ alkyl. Inembodiments, R¹ is substituted or unsubstituted methyl.

In embodiments, R¹ is substituted or unsubstituted C₁ alkyl. Inembodiments, R¹ is substituted or unsubstituted C₂ alkyl. Inembodiments, R¹ is substituted or unsubstituted C₃ alkyl. Inembodiments, R¹ is substituted or unsubstituted C₄ alkyl. Inembodiments, R¹ is substituted or unsubstituted C₅ alkyl. Inembodiments, R¹ is substituted or unsubstituted C₆ alkyl. Inembodiments, R¹ is substituted C₁ alkyl. In embodiments, R¹ issubstituted C₂ alkyl. In embodiments, R¹ is substituted C₃ alkyl. Inembodiments, R¹ is substituted C₄ alkyl. In embodiments, R¹ issubstituted C₅ alkyl. In embodiments, R¹ is substituted C₆ alkyl. Inembodiments, R¹ is unsubstituted C₁ alkyl. In embodiments, R¹ isunsubstituted C₂ alkyl. In embodiments, R¹ is unsubstituted C₃ alkyl. Inembodiments, R¹ is unsubstituted C₄ alkyl. In embodiments, R¹ isunsubstituted C₅ alkyl. In embodiments, R¹ is unsubstituted C₆ alkyl.

In embodiments, R¹ is R³¹-substituted or unsubstituted alkyl,R³¹-substituted or unsubstituted heteroalkyl, R³¹-substituted orunsubstituted cycloalkyl, R³¹-substituted or unsubstitutedheterocycloalkyl, R³¹-substituted or unsubstituted aryl, orR³¹-substituted or unsubstituted heteroaryl. In embodiments, R¹ isR³¹-substituted or unsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R³¹is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

R³¹ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂,—CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl,—OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃,—OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R³¹ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or—SO₄H. In embodiments, R³¹ is independently —SO₃H. In embodiments, R³¹is independently —PO₃H. In embodiments, R³¹ is independently —SO₂NH₂. Inembodiments, R³¹ is independently —SO₄H.

In embodiments, R¹ is substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g.,C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R¹is substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl, substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heterocycloalkyl,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl, orsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroaryl. In embodiments, R¹ is unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl.

In embodiments, R^(1A) is substituted or unsubstituted C₁-C₆ alkyl. Inembodiments, R^(1A) is substituted or unsubstituted C₁-C₃ alkyl. Inembodiments, R^(1A) is substituted or unsubstituted methyl.

In embodiments, R^(1A) is substituted or unsubstituted C₁ alkyl. Inembodiments, R^(1A) is substituted or unsubstituted C₂ alkyl. Inembodiments, R^(1A) is substituted or unsubstituted C₃ alkyl. Inembodiments, R^(1A) is substituted or unsubstituted C₄ alkyl. Inembodiments, R^(1A) is substituted or unsubstituted C₅ alkyl. Inembodiments, R^(1A) is substituted or unsubstituted C₆ alkyl. Inembodiments, R^(1A) is substituted C₁ alkyl. In embodiments, R^(1A) issubstituted C₂ alkyl. In embodiments, R^(1A) is substituted C₃ alkyl. Inembodiments, R^(1A) is substituted C₄ alkyl. In embodiments, R^(1A) issubstituted C₅ alkyl. In embodiments, R^(1A) is substituted C₆ alkyl. Inembodiments, R^(1A) is unsubstituted C₁ alkyl. In embodiments, R^(1A) isunsubstituted C₂ alkyl. In embodiments, R^(1A) is unsubstituted C₃alkyl. In embodiments, R^(1A) is unsubstituted C₄ alkyl. In embodiments,R^(1A) is unsubstituted C₅ alkyl. In embodiments, R^(1A) isunsubstituted C₆ alkyl.

In embodiments, R^(1A) is R^(31A)-substituted or unsubstituted alkyl,R^(31A)-substituted or unsubstituted heteroalkyl, R^(31A)-substituted orunsubstituted cycloalkyl, R^(31A)-substituted or unsubstitutedheterocycloalkyl, R^(31A)-substituted or unsubstituted aryl, orR^(31A)-substituted or unsubstituted heteroaryl.

R^(31A) is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂,—CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl,—OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃,—OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —N₃, unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄,or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstitutedaryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R^(1A) is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3membered, or 4 to 5 membered), substituted or unsubstituted cycloalkyl(e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstitutedheterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R^(1A) is substituted (e.g., substitutedwith a substituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted alkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroalkyl, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted cycloalkyl,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheterocycloalkyl, substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted aryl, or substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroaryl. In embodiments, R^(1A) is unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen,halogen, —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CHF₂,—CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂, —COOH, —CONH₂, or —SH. In embodiments,R¹, R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen. In embodiments,R¹, R⁴, R⁵, R⁶, and R⁷ are each independently halogen. In embodiments,R¹, R⁴, R⁵, R⁶, and R⁷ are each independently —CF₃. In embodiments, R¹,R⁴, R⁵, R⁶, and R⁷ are each independently —CBr₃. In embodiments, R¹, R⁴,R⁵, R⁶, and R⁷ are each independently —CCl₃. In embodiments, R¹, R⁴, R⁵,R⁶, and R⁷ are each independently —CI₃. In embodiments, R¹, R⁴, R⁵, R⁶,and R⁷ are each independently —CHF₂. In embodiments, R¹, R⁴, R⁵, R⁶, andR⁷ are each independently —CHBr₂. In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷are each independently —CHCl₂. In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷are each independently —CHI₂. In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷ areeach independently —CHF₂. In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷ areeach independently —CH₂Br. In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷ areeach independently —CH₂Cl. In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷ areeach independently —CH₂I. In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷ areeach independently —OH. In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷ are eachindependently —NH₂. In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷ are eachindependently —COOH. In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷ are eachindependently —CONH₂. In embodiments, R¹, R⁴, R⁵, R⁶, and R⁷ are eachindependently —SH.

In embodiments, R¹ is independently hydrogen, halogen, —CF₃, —CCl₃,—CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, or —N₃. In embodiments, R¹ isindependently hydrogen. In embodiments, R¹ is independently halogen. Inembodiments, R¹ is independently —CF₃. In embodiments, R¹ isindependently-CCl₃. In embodiments, R¹ is independently —CI₃. Inembodiments, R¹ is independently —CBr₃. In embodiments, R¹ isindependently —CHF₂. In embodiments, R¹ is independently —CHCl₂. Inembodiments, R¹ is independently —CHI₂. In embodiments, R¹ isindependently —CHBr₂. In embodiments, R¹ is independently —CH₂F. Inembodiments, R¹ is independently —CH₂Cl. In embodiments, R¹ isindependently —CH₂I. In embodiments, R¹ is independently —CH₂Br. Inembodiments, R¹ is independently —OCH₂F. In embodiments, R¹ isindependently —OCH₂Cl. In embodiments, R¹ is independently —OCH₂I. Inembodiments, R¹ is independently —OCH₂Br. In embodiments, R¹ isindependently —OCHF₂. In embodiments, R¹ is independently —OCHCl₂. Inembodiments, R¹ is independently —OCHI₂. In embodiments, R¹ isindependently —OCHBr₂. In embodiments, R¹ is independently —OCF₃. Inembodiments, R¹ is independently —OCCl₃. In embodiments, R¹ isindependently —OCI₃. In embodiments, R¹ is independently —OCBr₃. Inembodiments, R¹ is independently —CN. In embodiments, R¹ isindependently —OH. In embodiments, R¹ is independently —NH₂. Inembodiments, R¹ is independently —COOH. In embodiments, R¹ isindependently —CONH₂. In embodiments, R¹ is independently —NO₂. Inembodiments, R¹ is independently —SH. In embodiments, R¹ isindependently —SO₃H. In embodiments, R¹ is independently —SO₄H. Inembodiments, R¹ is independently —SO₂NH₂. In embodiments, R¹ isindependently —NHNH₂. In embodiments, R¹ is independently —ONH₂. Inembodiments, R¹ is independently —NHC═(O)NHNH₂. In embodiments, R¹ isindependently —NHC═(O)NH₂. In embodiments, R¹ is independently —NHSO₂H.In embodiments, R¹ is independently —NHC═(O)H. In embodiments, R¹ isindependently —NHC(O)OH. In embodiments, R¹ is independently —NHOH.

In embodiments, R¹ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkyl. In embodiments, R¹ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkyl. In embodiments, R¹ is unsubstitutedalkyl. In embodiments, R¹ is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R¹ is substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R¹ isunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R² is R³²-substituted or unsubstituted alkyl, orR³²-substituted or unsubstituted heteroalkyl. In embodiments, R² isR³²-substituted or unsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R³²is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

R³² is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂,—CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl,—OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃,—OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R³² is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or—SO₄H. In embodiments, R³² is independently —SO₃H. In embodiments, R³²is independently —PO₃H. In embodiments, R³² is independently —SO₂NH₂. Inembodiments, R³² is independently —SO₄H.

In embodiments, R² is independently substituted or unsubstituted C₁-C₆alkyl. In embodiments, R² is independently substituted or unsubstitutedC₁-C₃ alkyl. In embodiments, R² is independently substituted orunsubstituted methyl. In embodiments, R² is independently substituted orunsubstituted ethyl. In embodiments, R² is independently substituted orunsubstituted C₃ alkyl (e.g., n-propyl or isopropyl).

In embodiments, R² is independently substituted or unsubstituted C₁alkyl. In embodiments, R² is independently substituted or unsubstitutedC₂ alkyl. In embodiments, R² is independently substituted orunsubstituted C₃ alkyl. In embodiments, R² is independently substitutedor unsubstituted C₄ alkyl. In embodiments, R² is independentlysubstituted or unsubstituted C₅ alkyl. In embodiments, R² isindependently substituted or unsubstituted C₆ alkyl. In embodiments, R²is independently substituted C₁ alkyl. In embodiments, R² isindependently substituted C₂ alkyl. In embodiments, R² is independentlysubstituted C₃ alkyl. In embodiments, R² is independently substituted C₄alkyl. In embodiments, R² is independently substituted C₅ alkyl. Inembodiments, R² is independently substituted C₆ alkyl. In embodiments,R² is independently unsubstituted C₁ alkyl. In embodiments, R² isindependently unsubstituted C₂ alkyl. In embodiments, R² isindependently unsubstituted C₃ alkyl. In embodiments, R² isindependently unsubstituted C₄ alkyl. In embodiments, R² isindependently unsubstituted C₅ alkyl. In embodiments, R² isindependently unsubstituted C₆ alkyl.

In embodiments, R² is substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂) or substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3membered, or 4 to 5 membered). In embodiments, R² is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl, or substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl. Inembodiments, R² is unsubstituted alkyl or unsubstituted heteroalkyl.

In embodiments, R² is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkyl. In embodiments, R² is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkyl. In embodiments, R² is unsubstitutedalkyl. In embodiments, R² is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R² is substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R² isunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R³ is R³³-substituted or unsubstituted alkyl, orR³³-substituted or unsubstituted heteroalkyl. In embodiments, R³ isR³³-substituted or unsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R³³is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

R³³ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂,—CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl,—OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃,—OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R³³ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or—SO₄H. In embodiments, R³³ is independently —SO₃H. In embodiments, R³³is independently —PO₃H. In embodiments, R³³ is independently —SO₂NH₂. Inembodiments, R³³ is independently —SO₄H.

In embodiments, R³ is substituted or unsubstituted C₁-C₆ alkyl. Inembodiments, R³ is substituted or unsubstituted C₁-C₃ alkyl. Inembodiments, R³ is substituted or unsubstituted methyl. In embodiments,R³ is substituted or unsubstituted ethyl. In embodiments, R³ issubstituted or unsubstituted C₃ alkyl (e.g., n-propyl or isopropyl).

In embodiments, R³ is independently substituted or unsubstituted C₁alkyl. In embodiments, R³ is independently substituted or unsubstitutedC₂ alkyl. In embodiments, R³ is independently substituted orunsubstituted C₃ alkyl. In embodiments, R³ is independently substitutedor unsubstituted C₄ alkyl. In embodiments, R³ is independentlysubstituted or unsubstituted C₅ alkyl. In embodiments, R³ isindependently substituted or unsubstituted C₆ alkyl. In embodiments, R³is independently substituted C₁ alkyl. In embodiments, R³ isindependently substituted C₂ alkyl. In embodiments, R³ is independentlysubstituted C₃ alkyl. In embodiments, R³ is independently substituted C₄alkyl. In embodiments, R³ is independently substituted C₅ alkyl. Inembodiments, R³ is independently substituted C₆ alkyl. In embodiments,R³ is independently unsubstituted C₁ alkyl. In embodiments, R³ isindependently unsubstituted C₂ alkyl. In embodiments, R³ isindependently unsubstituted C₃ alkyl. In embodiments, R³ isindependently unsubstituted C₄ alkyl. In embodiments, R³ isindependently unsubstituted C₅ alkyl. In embodiments, R³ isindependently unsubstituted C₆ alkyl.

In embodiments, R³ is substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), or substituted or unsubstituted heteroalkyl(e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3membered, or 4 to 5 membered). In embodiments, R³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl, or substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl. Inembodiments, R³ is unsubstituted alkyl, unsubstituted heteroalkyl.

In embodiments, R³ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkyl. In embodiments, R³ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkyl. In embodiments, R³ is unsubstitutedalkyl. In embodiments, R³ is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R³ is substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R³ isunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R⁴ is independently hydrogen, halogen, —CF₃, —CCl₃,—CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, or —N₃. In embodiments, R⁴ isindependently hydrogen. In embodiments, R⁴ is independently halogen. Inembodiments, R⁴ is independently —CF₃. In embodiments, R⁴ isindependently —CCl₃. In embodiments, R⁴ is independently —CI₃. Inembodiments, R⁴ is independently —CBr₃. In embodiments, R⁴ isindependently —CHF₂. In embodiments, R⁴ is independently —CHCl₂. Inembodiments, R⁴ is independently —CHI₂. In embodiments, R⁴ isindependently —CHBr₂. In embodiments, R⁴ is independently —CH₂F. Inembodiments, R⁴ is independently —CH₂Cl. In embodiments, R⁴ isindependently —CH₂I. In embodiments, R⁴ is independently —CH₂Br. Inembodiments, R⁴ is independently —OCH₂F. In embodiments, R⁴ isindependently —OCH₂Cl. In embodiments, R⁴ is independently —OCH₂I. Inembodiments, R⁴ is independently —OCH₂Br. In embodiments, R⁴ isindependently —OCHF₂. In embodiments, R⁴ is independently —OCHCl₂. Inembodiments, R⁴ is independently —OCHI₂. In embodiments, R⁴ isindependently —OCHBr₂. In embodiments, R⁴ is independently —OCF₃. Inembodiments, R⁴ is independently —OCCl₃. In embodiments, R⁴ isindependently —OCI₃. In embodiments, R⁴ is independently —OCBr₃. Inembodiments, R⁴ is independently —CN. In embodiments, R⁴ isindependently —OH. In embodiments, R⁴ is independently —NH₂. Inembodiments, R⁴ is independently —COOH. In embodiments, R⁴ isindependently —CONH₂. In embodiments, R⁴ is independently —NO₂. Inembodiments, R⁴ is independently —SH. In embodiments, R⁴ isindependently —SO₃H. In embodiments, R⁴ is independently —SO₄H. Inembodiments, R⁴ is independently —SO₂NH₂. In embodiments, R⁴ isindependently —NHNH₂. In embodiments, R⁴ is independently —ONH₂. Inembodiments, R⁴ is independently —NHC═(O)NHNH₂. In embodiments, R⁴ isindependently —NHC═(O)NH₂. In embodiments, R⁴ is independently —NHSO₂H.In embodiments, R⁴ is independently —NHC═(O)H. In embodiments, R⁴ isindependently —NHC(O)OH. In embodiments, R⁴ is independently —NHOH.

In embodiments, R⁴ is R³⁴-substituted or unsubstituted alkyl,R³⁴-substituted or unsubstituted heteroalkyl, R³⁴-substituted orunsubstituted cycloalkyl, R³⁴-substituted or unsubstitutedheterocycloalkyl, R³⁴-substituted or unsubstituted aryl, orR³⁴-substituted or unsubstituted heteroaryl.

R³⁴ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂,—CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl,—OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃,—OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R³⁴ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or—SO₄H. In embodiments, R³⁴ is independently —SO₃H. In embodiments, R³⁴is independently —PO₃H. In embodiments, R³⁴ is independently —SO₂NH₂. Inembodiments, R³⁴ is independently —SO₄H.

In embodiments, R⁴ is hydrogen, or substituted or unsubstituted C₁-C₆alkyl. In embodiments, R⁴ is hydrogen. In embodiments, R⁴ is substitutedor unsubstituted C₁-C₆ alkyl. In embodiments, R⁴ is substituted orunsubstituted C₁ alkyl. In embodiments, R⁴ is substituted orunsubstituted C₂ alkyl. In embodiments, R⁴ is substituted orunsubstituted C₃ alkyl. In embodiments, R⁴ is substituted orunsubstituted C₄ alkyl. In embodiments, R⁴ is substituted orunsubstituted C₅ alkyl. In embodiments, R⁴ is substituted orunsubstituted C₆ alkyl. In embodiments, R⁴ is substituted C₁ alkyl. Inembodiments, R⁴ is substituted C₂ alkyl. In embodiments, R⁴ issubstituted C₃ alkyl. In embodiments, R⁴ is substituted C₄ alkyl. Inembodiments, R⁴ is substituted C₅ alkyl. In embodiments, R⁴ issubstituted C₆ alkyl. In embodiments, R⁴ is unsubstituted C₁ alkyl. Inembodiments, R⁴ is unsubstituted C₂ alkyl. In embodiments, R⁴ isunsubstituted C₃ alkyl. In embodiments, R⁴ is unsubstituted C₄ alkyl. Inembodiments, R⁴ is unsubstituted C₅ alkyl. In embodiments, R⁴ isunsubstituted C₆ alkyl. In embodiments, R⁴ is R³⁴-substituted orunsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R³⁴ is independently—PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

In embodiments, R⁴ is substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g.,C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R⁴is substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl, substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heterocycloalkyl,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl, orsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroaryl. In embodiments, R⁴ is unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl.

In embodiments, R⁴ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkyl. In embodiments, R⁴ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkyl. In embodiments, R⁴ is unsubstitutedalkyl. In embodiments, R⁴ is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁴ is substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁴ isunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R⁵ is independently hydrogen, halogen, —CF₃, —CCl₃,—CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, or —N₃. In embodiments, R⁵ isindependently hydrogen. In embodiments, R⁵ is independently halogen. Inembodiments, R⁵ is independently —CF₃. In embodiments, R⁵ isindependently —CCl₃. In embodiments, R⁵ is independently —CI₃. Inembodiments, R⁵ is independently —CBr₃. In embodiments, R⁵ isindependently —CHF₂. In embodiments, R⁵ is independently —CHCl₂. Inembodiments, R⁵ is independently —CHI₂. In embodiments, R⁵ isindependently —CHBr₂. In embodiments, R⁵ is independently —CH₂F. Inembodiments, R⁵ is independently —CH₂Cl. In embodiments, R⁵ isindependently —CH₂I. In embodiments, R⁵ is independently —CH₂Br. Inembodiments, R⁵ is independently —OCH₂F. In embodiments, R⁵ isindependently —OCH₂Cl. In embodiments, R⁵ is independently —OCH₂I. Inembodiments, R⁵ is independently —OCH₂Br. In embodiments, R⁵ isindependently —OCHF₂. In embodiments, R⁵ is independently —OCHCl₂. Inembodiments, R⁵ is independently —OCHI₂. In embodiments, R⁵ isindependently —OCHBr₂. In embodiments, R⁵ is independently —OCF₃. Inembodiments, R⁵ is independently —OCCl₃. In embodiments, R⁵ isindependently —OCI₃. In embodiments, R⁵ is independently —OCBr₃. Inembodiments, R⁵ is independently —CN. In embodiments, R⁵ isindependently —OH. In embodiments, R⁵ is independently —NH₂. Inembodiments, R⁵ is independently —COOH. In embodiments, R⁵ isindependently —CONH₂. In embodiments, R⁵ is independently —NO₂. Inembodiments, R⁵ is independently —SH. In embodiments, R⁵ isindependently —SO₃H. In embodiments, R⁵ is independently —SO₄H. Inembodiments, R⁵ is independently —SO₂NH₂. In embodiments, R⁵ isindependently —NHNH₂. In embodiments, R⁵ is independently —ONH₂. Inembodiments, R⁵ is independently —NHC═(O)NHNH₂. In embodiments, R⁵ isindependently —NHC═(O)NH₂. In embodiments, R⁵ is independently —NHSO₂H.In embodiments, R⁵ is independently —NHC═(O)H. In embodiments, R⁵ isindependently —NHC(O)OH. In embodiments, R⁵ is independently —NHOH.

In embodiments, R⁵ is R³⁵-substituted or unsubstituted alkyl,R³⁵-substituted or unsubstituted heteroalkyl, R³⁵-substituted orunsubstituted cycloalkyl, R³⁵-substituted or unsubstitutedheterocycloalkyl, R³⁵-substituted or unsubstituted aryl, orR³⁵-substituted or unsubstituted heteroaryl.

R³⁵ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂,—CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl,—OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃,—OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R³⁵ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or—SO₄H. In embodiments, R³⁵ is independently —SO₃H. In embodiments, R³⁵is independently —PO₃H. In embodiments, R³⁵ is independently —SO₂NH₂. Inembodiments, R³⁵ is independently —SO₄H.

In embodiments, R⁵ is hydrogen, or substituted or unsubstituted C₁-C₆alkyl. In embodiments, R⁵ is hydrogen. In embodiments, R⁵ is substitutedor unsubstituted C₁-C₆ alkyl. In embodiments, R⁵ is substituted orunsubstituted C₁ alkyl. In embodiments, R⁵ is substituted orunsubstituted C₂ alkyl. In embodiments, R⁵ is substituted orunsubstituted C₃ alkyl. In embodiments, R⁵ is substituted orunsubstituted C₄ alkyl. In embodiments, R⁵ is substituted orunsubstituted C₅ alkyl. In embodiments, R⁵ is substituted orunsubstituted C₆ alkyl. In embodiments, R⁵ is substituted C₁ alkyl. Inembodiments, R⁵ is substituted C₂ alkyl. In embodiments, R⁵ issubstituted C₃ alkyl. In embodiments, R⁵ is substituted C₄ alkyl. Inembodiments, R⁵ is substituted C₅ alkyl. In embodiments, R⁵ issubstituted C₆ alkyl. In embodiments, R⁵ is unsubstituted C₁ alkyl. Inembodiments, R⁵ is unsubstituted C₂ alkyl. In embodiments, R⁵ isunsubstituted C₃ alkyl. In embodiments, R⁵ is unsubstituted C₄ alkyl. Inembodiments, R⁵ is unsubstituted C₅ alkyl. In embodiments, R⁵ isunsubstituted C₆ alkyl. In embodiments, R⁵ is R³⁵-substituted orunsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R³⁵ is independently—PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

In embodiments, R⁵ is substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g.,C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R⁵is substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl, substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heterocycloalkyl,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl, orsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroaryl. In embodiments, R⁵ is unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl.

In embodiments, R⁵ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkyl. In embodiments, R⁵ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkyl. In embodiments, R⁵ is unsubstitutedalkyl. In embodiments, R⁵ is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁵ is substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁵ isunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R⁶ is independently hydrogen, halogen, —CF₃, —CCl₃,—CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, or —N₃. In embodiments, R⁶ isindependently hydrogen. In embodiments, R⁶ is independently halogen. Inembodiments, R⁶ is independently —CF₃. In embodiments, R⁶ isindependently —CCl₃. In embodiments, R⁶ is independently —CI₃. Inembodiments, R⁶ is independently —CBr₃. In embodiments, R⁶ isindependently —CHF₂. In embodiments, R⁶ is independently —CHCl₂. Inembodiments, R⁶ is independently —CHI₂. In embodiments, R⁶ isindependently —CHBr₂. In embodiments, R⁶ is independently —CH₂F. Inembodiments, R⁶ is independently —CH₂Cl. In embodiments, R⁶ isindependently —CH₂I. In embodiments, R⁶ is independently —CH₂Br. Inembodiments, R⁶ is independently —OCH₂F. In embodiments, R⁶ isindependently —OCH₂Cl. In embodiments, R⁶ is independently —OCH₂I. Inembodiments, R⁶ is independently —OCH₂Br. In embodiments, R⁶ isindependently —OCHF₂. In embodiments, R⁶ is independently —OCHCl₂. Inembodiments, R⁶ is independently —OCHI₂. In embodiments, R⁶ isindependently —OCHBr₂. In embodiments, R⁶ is independently —OCF₃. Inembodiments, R⁶ is independently —OCCl₃. In embodiments, R⁶ isindependently —OCI₃. In embodiments, R⁶ is independently —OCBr₃. Inembodiments, R⁶ is independently —CN. In embodiments, R⁶ isindependently —OH. In embodiments, R⁶ is independently —NH₂. Inembodiments, R⁶ is independently —COOH. In embodiments, R⁶ isindependently —CONH₂. In embodiments, R⁶ is independently —NO₂. Inembodiments, R⁶ is independently —SH. In embodiments, R⁶ isindependently —SO₃H. In embodiments, R⁶ is independently —SO₄H. Inembodiments, R⁶ is independently —SO₂NH₂. In embodiments, R⁶ isindependently —NHNH₂. In embodiments, R⁶ is independently —ONH₂. Inembodiments, R⁶ is independently —NHC═(O)NHNH₂. In embodiments, R⁶ isindependently —NHC═(O)NH₂. In embodiments, R⁶ is independently —NHSO₂H.In embodiments, R⁶ is independently —NHC═(O)H. In embodiments, R⁶ isindependently —NHC(O)OH. In embodiments, R⁶ is independently —NHOH.

In embodiments, R⁶ is R³⁶-substituted or unsubstituted alkyl,R³⁶-substituted or unsubstituted heteroalkyl, R³⁶-substituted orunsubstituted cycloalkyl, R³⁶-substituted or unsubstitutedheterocycloalkyl, R³⁶-substituted or unsubstituted aryl, orR³⁶-substituted or unsubstituted heteroaryl.

R³⁶ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂,—CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl,—OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃,—OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R³⁶ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or—SO₄H. In embodiments, R³⁶ is independently —SO₃H. In embodiments, R³⁶is independently —PO₃H. In embodiments, R³⁶ is independently —SO₂NH₂. Inembodiments, R³⁶ is independently —SO₄H.

In embodiments, R⁶ is hydrogen, or substituted or unsubstituted C₁-C₆alkyl. In embodiments, R⁶ is hydrogen. In embodiments, R⁶ is substitutedor unsubstituted C₁-C₆ alkyl. In embodiments, R⁶ is substituted orunsubstituted C₁ alkyl. In embodiments, R⁶ is substituted orunsubstituted C₂ alkyl. In embodiments, R⁶ is substituted orunsubstituted C₃ alkyl. In embodiments, R⁶ is substituted orunsubstituted C₄ alkyl. In embodiments, R⁶ is substituted orunsubstituted C₅ alkyl. In embodiments, R⁶ is substituted orunsubstituted C₆ alkyl. In embodiments, R⁶ is substituted C₁ alkyl. Inembodiments, R⁶ is substituted C₂ alkyl. In embodiments, R⁶ issubstituted C₃ alkyl. In embodiments, R⁶ is substituted C₄ alkyl. Inembodiments, R⁶ is substituted C₅ alkyl. In embodiments, R⁶ issubstituted C₆ alkyl. In embodiments, R⁶ is unsubstituted C₁ alkyl. Inembodiments, R⁶ is unsubstituted C₂ alkyl. In embodiments, R⁶ isunsubstituted C₃ alkyl. In embodiments, R⁶ is unsubstituted C₄ alkyl. Inembodiments, R⁶ is unsubstituted C₅ alkyl. In embodiments, R⁶ isunsubstituted C₆ alkyl. In embodiments, R⁶ is R³⁶-substituted orunsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R³⁶ is independently—PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

In embodiments, R⁶ is substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g.,C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R⁶is substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl, substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heterocycloalkyl,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl, orsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroaryl. In embodiments, R⁶ is unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl.

In embodiments, R⁶ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkyl. In embodiments, R⁶ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkyl. In embodiments, R⁶ is unsubstitutedalkyl. In embodiments, R⁶ is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁶ is substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁶ isunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R⁷ is independently hydrogen, halogen, —CF₃, —CCl₃,—CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, or —N₃. In embodiments, R⁷ isindependently hydrogen. In embodiments, R⁷ is independently halogen. Inembodiments, R⁷ is independently —CF₃. In embodiments, R⁷ isindependently —CCl₃. In embodiments, R⁷ is independently —CI₃. Inembodiments, R⁷ is independently —CBr₃. In embodiments, R⁷ isindependently —CHF₂. In embodiments, R⁷ is independently —CHCl₂. Inembodiments, R⁷ is independently —CHI₂. In embodiments, R⁷ isindependently —CHBr₂. In embodiments, R⁷ is independently —CH₂F. Inembodiments, R⁷ is independently —CH₂Cl. In embodiments, R⁷ isindependently —CH₂I. In embodiments, R⁷ is independently —CH₂Br. Inembodiments, R⁷ is independently —OCH₂F. In embodiments, R⁷ isindependently —OCH₂Cl. In embodiments, R⁷ is independently —OCH₂I. Inembodiments, R⁷ is independently —OCH₂Br. In embodiments, R⁷ isindependently —OCHF₂. In embodiments, R⁷ is independently —OCHCl₂. Inembodiments, R⁷ is independently —OCHI₂. In embodiments, R⁷ isindependently —OCHBr₂. In embodiments, R⁷ is independently —OCF₃. Inembodiments, R⁷ is independently —OCCl₃. In embodiments, R⁷ isindependently —OCI₃. In embodiments, R⁷ is independently —OCBr₃. Inembodiments, R⁷ is independently —CN. In embodiments, R⁷ isindependently —OH. In embodiments, R⁷ is independently —NH₂. Inembodiments, R⁷ is independently —COOH. In embodiments, R⁷ isindependently —CONH₂. In embodiments, R⁷ is independently —NO₂. Inembodiments, R⁷ is independently —SH. In embodiments, R⁷ isindependently —SO₃H. In embodiments, R⁷ is independently —SO₄H. Inembodiments, R⁷ is independently —SO₂NH₂. In embodiments, R⁷ isindependently —NHNH₂. In embodiments, R⁷ is independently —ONH₂. Inembodiments, R⁷ is independently —NHC═(O)NHNH₂. In embodiments, R⁷ isindependently —NHC═(O)NH₂. In embodiments, R⁷ is independently —NHSO₂H.In embodiments, R⁷ is independently —NHC═(O)H. In embodiments, R⁷ isindependently —NHC(O)OH. In embodiments, R⁷ is independently —NHOH.

In embodiments, R⁷ is R³⁷-substituted or unsubstituted alkyl,R³⁷-substituted or unsubstituted heteroalkyl, R³⁷-substituted orunsubstituted cycloalkyl, R³⁷-substituted or unsubstitutedheterocycloalkyl, R³⁷-substituted or unsubstituted aryl, orR³⁷-substituted or unsubstituted heteroaryl.

R³⁷ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂,—CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl,—OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃,—OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂,—NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H,—NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R³⁷ is independently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or—SO₄H. In embodiments, R³⁷ is independently —SO₃H. In embodiments, R³⁷is independently —PO₃H. In embodiments, R³⁷ is independently —SO₂NH₂. Inembodiments, R³⁷ is independently —SO₄H.

In embodiments, R⁷ is hydrogen, or substituted or unsubstituted C₁-C₆alkyl. In embodiments, R⁷ is hydrogen. In embodiments, R⁷ is substitutedor unsubstituted C₁-C₆ alkyl. In embodiments, R⁷ is substituted orunsubstituted C₁ alkyl. In embodiments, R⁷ is substituted orunsubstituted C₂ alkyl. In embodiments, R⁷ is substituted orunsubstituted C₃ alkyl. In embodiments, R⁷ is substituted orunsubstituted C₄ alkyl. In embodiments, R⁷ is substituted orunsubstituted C₅ alkyl. In embodiments, R⁷ is substituted orunsubstituted C₆ alkyl. In embodiments, R⁷ is substituted C₁ alkyl. Inembodiments, R⁷ is substituted C₂ alkyl. In embodiments, R⁷ issubstituted C₃ alkyl. In embodiments, R⁷ is substituted C₄ alkyl. Inembodiments, R⁷ is substituted C₅ alkyl. In embodiments, R⁷ issubstituted C₆ alkyl. In embodiments, R⁷ is unsubstituted C₁ alkyl. Inembodiments, R⁷ is unsubstituted C₂ alkyl. In embodiments, R⁷ isunsubstituted C₃ alkyl. In embodiments, R⁷ is unsubstituted C₄ alkyl. Inembodiments, R⁷ is unsubstituted C₅ alkyl. In embodiments, R⁷ isunsubstituted C₆ alkyl. In embodiments, R⁷ is R³⁷-substituted orunsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R³⁷ is independently—PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

In embodiments, R⁷ is substituted or unsubstituted alkyl (e.g., C₁-C₈,C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstituted heteroalkyl (e.g.,2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4to 5 membered), substituted or unsubstituted cycloalkyl (e.g., C₃-C₈,C₃-C₆, C₄-C₆, or C₅-C₆), substituted or unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered), substituted or unsubstituted aryl (e.g.,C₆-C₁₀ or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, R⁷is substituted (e.g., substituted with a substituent group, asize-limited substituent group, or lower substituent group) orunsubstituted alkyl, substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroalkyl, substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted cycloalkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heterocycloalkyl,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstituted aryl, orsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroaryl. In embodiments, R⁷ is unsubstituted alkyl, unsubstitutedheteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,unsubstituted aryl, or unsubstituted heteroaryl.

In embodiments, R⁷ is substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted alkyl. In embodiments, R⁷ is substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) alkyl. In embodiments, R⁷ is unsubstitutedalkyl. In embodiments, R⁷ is substituted or unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁷ is substituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂). In embodiments, R⁷ isunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂).

In embodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstituted 3 to 6membered heterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted 3 membered heterocycloalkyl. In embodiments, R⁴ and R⁵substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstituted 5 memberedheterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted 6 membered heterocycloalkyl. In embodiments, R⁴ and R⁵substituents bonded to the same nitrogen atom may optionally be joinedto form an unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted 3 memberedheterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bonded to thesame nitrogen atom may optionally be joined to form an unsubstituted 4membered heterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bondedto the same nitrogen atom may optionally be joined to form anunsubstituted 5 membered heterocycloalkyl. In embodiments, R⁴ and R⁵substituents bonded to the same nitrogen atom may optionally be joinedto form an unsubstituted 6 membered heterocycloalkyl. In embodiments, R⁴and R⁵ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted 3 membered heterocycloalkyl.In embodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted 4 memberedheterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted 5membered heterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bondedto the same nitrogen atom may optionally be joined to form a substituted6 membered heterocycloalkyl.

In embodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atommay optionally be joined to form an R³⁴-substituted or unsubstituted 3to 6 membered heterocycloalkyl. In embodiments, R⁴ and R⁵ substituentsbonded to the same nitrogen atom may optionally be joined to form anR³⁴-substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R³⁴-substituted or unsubstituted 4membered heterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁴-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R³⁴-substituted or unsubstituted 6membered heterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁴-substituted 3 to 6 membered heterocycloalkyl. In embodiments, R⁴ andR⁵ substituents bonded to the same nitrogen atom may optionally bejoined to form an R³⁴-substituted 3 membered heterocycloalkyl. Inembodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R⁴-substituted 4 memberedheterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bonded to thesame nitrogen atom may optionally be joined to form an R³⁴-substituted 5membered heterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁴-substituted 6 membered heterocycloalkyl.

In embodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atommay optionally be joined to form an R³⁵-substituted or unsubstituted 3to 6 membered heterocycloalkyl. In embodiments, R⁴ and R⁵ substituentsbonded to the same nitrogen atom may optionally be joined to form anR³⁵-substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R³⁵-substituted or unsubstituted 4membered heterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁵-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R³⁵-substituted or unsubstituted 6membered heterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁵-substituted 3 to 6 membered heterocycloalkyl. In embodiments, R⁴ andR⁵ substituents bonded to the same nitrogen atom may optionally bejoined to form an R³⁵-substituted 3 membered heterocycloalkyl. Inembodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R³⁵-substituted 4 memberedheterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bonded to thesame nitrogen atom may optionally be joined to form an R³⁵-substituted 5membered heterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁵-substituted 6 membered heterocycloalkyl.

In embodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl. In embodiments, R⁴and R⁵ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group)heterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bonded to thesame nitrogen atom may optionally be joined to form an unsubstitutedheterocycloalkyl. In embodiments, R⁴ and R⁵ substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R⁴ and R⁵ substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).In embodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atommay optionally be joined to form an unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered).

In embodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstituted 3 to 6membered heterocycloalkyl.

In embodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted or unsubstituted 3 to 6membered heterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bondedto the same nitrogen atom may optionally be joined to form a substitutedor unsubstituted 3 membered heterocycloalkyl. In embodiments, R⁶ and R⁷substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstituted 5 memberedheterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted 6 membered heterocycloalkyl. In embodiments, R⁶ and R⁷substituents bonded to the same nitrogen atom may optionally be joinedto form an unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form an unsubstituted 3 memberedheterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bonded to thesame nitrogen atom may optionally be joined to form an unsubstituted 4membered heterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bondedto the same nitrogen atom may optionally be joined to form anunsubstituted 5 membered heterocycloalkyl. In embodiments, R⁶ and R⁷substituents bonded to the same nitrogen atom may optionally be joinedto form an unsubstituted 6 membered heterocycloalkyl. In embodiments, R⁶and R⁷ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted 3 membered heterocycloalkyl.In embodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted 4 memberedheterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted 5membered heterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bondedto the same nitrogen atom may optionally be joined to form a substituted6 membered heterocycloalkyl.

In embodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atommay optionally be joined to form an R³⁶-substituted or unsubstituted 3to 6 membered heterocycloalkyl. In embodiments, R⁶ and R⁷ substituentsbonded to the same nitrogen atom may optionally be joined to form anR³⁶-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R³⁶-substituted or unsubstituted 3membered heterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁶-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R³⁶-substituted or unsubstituted 5membered heterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁶-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R³⁶-substituted 3 to 6 memberedheterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bonded to thesame nitrogen atom may optionally be joined to form an R³⁶-substituted 3membered heterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁶-substituted 4 membered heterocycloalkyl. In embodiments, R⁶ and R⁷substituents bonded to the same nitrogen atom may optionally be joinedto form an R³⁶-substituted 5 membered heterocycloalkyl. In embodiments,R⁶ and R⁷ substituents bonded to the same nitrogen atom may optionallybe joined to form an R³⁶-substituted 6 membered heterocycloalkyl.

In embodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atommay optionally be joined to form an R³⁷-substituted or unsubstituted 3to 6 membered heterocycloalkyl. In embodiments, R⁶ and R⁷ substituentsbonded to the same nitrogen atom may optionally be joined to form anR³⁷-substituted or unsubstituted 3 to 6 membered heterocycloalkyl. Inembodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R³⁷-substituted or unsubstituted 3membered heterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁷-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R³⁷-substituted or unsubstituted 5membered heterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁷-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form an R³⁷-substituted 3 to 6 memberedheterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bonded to thesame nitrogen atom may optionally be joined to form an R³⁷-substituted 3membered heterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bondedto the same nitrogen atom may optionally be joined to form anR³⁷-substituted 4 membered heterocycloalkyl. In embodiments, R⁶ and R⁷substituents bonded to the same nitrogen atom may optionally be joinedto form an R³⁷-substituted 5 membered heterocycloalkyl. In embodiments,R⁶ and R⁷ substituents bonded to the same nitrogen atom may optionallybe joined to form an R³⁷-substituted 6 membered heterocycloalkyl.

In embodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl. In embodiments, R⁶and R⁷ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group)heterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bonded to thesame nitrogen atom may optionally be joined to form an unsubstitutedheterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R⁶ and R⁷ substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).In embodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atommay optionally be joined to form an unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered).

In embodiments, R⁴ and R⁹ substituents may optionally be joined to forma substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orsubstituted or unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁴ and R⁹ substituents may optionally be joined to forma substituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form asubstituted or unsubstituted 4 to 7 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form asubstituted or unsubstituted 4 to 6 membered heterocycloalkyl.

In embodiments, R⁴ and R⁹ substituents may optionally be joined to forma substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form asubstituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form asubstituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form asubstituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form asubstituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form asubstituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form asubstituted 3 membered heterocycloalkyl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form a substituted 4 memberedheterocycloalkyl. In embodiments, R⁴ and R⁹ substituents may optionallybe joined to form a substituted 5 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form asubstituted 6 membered heterocycloalkyl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form a substituted 7 memberedheterocycloalkyl. In embodiments, R⁴ and R⁹ substituents may optionallybe joined to form a substituted 8 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anunsubstituted 3 membered heterocycloalkyl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form an unsubstituted 4membered heterocycloalkyl. In embodiments, R⁴ and R⁹ substituents mayoptionally be joined to form an unsubstituted 5 memberedheterocycloalkyl. In embodiments, R⁴ and R⁹ substituents may optionallybe joined to form an unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anunsubstituted 7 membered heterocycloalkyl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form an unsubstituted 8membered heterocycloalkyl.

In embodiments, R⁴ and R⁹ substituents may optionally be joined to forman R³⁴-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orR³⁴-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁴-substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁴-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁴-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁴-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁴-substituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁴-substituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁴-substituted 3 membered heterocycloalkyl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form an R³⁴-substituted 4membered heterocycloalkyl. In embodiments, R⁴ and R⁹ substituents mayoptionally be joined to form an R³⁴-substituted 5 memberedheterocycloalkyl. In embodiments, R⁴ and R⁹ substituents may optionallybe joined to form an R³⁴-substituted 6 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁴-substituted 7 membered heterocycloalkyl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form an R³⁴-substituted 8membered heterocycloalkyl.

In embodiments, R⁴ and R⁹ substituents may optionally be joined to forman R³⁹-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orR³⁹-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁹-substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁹-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁹-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁹-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁹-substituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁹-substituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁹-substituted 3 membered heterocycloalkyl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form an R³⁹-substituted 4membered heterocycloalkyl. In embodiments, R⁴ and R⁹ substituents mayoptionally be joined to form an R³⁹-substituted 5 memberedheterocycloalkyl. In embodiments, R⁴ and R⁹ substituents may optionallybe joined to form an R³⁹-substituted 6 membered heterocycloalkyl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁹-substituted 7 membered heterocycloalkyl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form an R³⁹-substituted 8membered heterocycloalkyl.

In embodiments, R⁴ and R⁹ substituents may optionally be joined to forma substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form asubstituted or unsubstituted 5 membered heteroaryl. In embodiments, R⁴and R⁹ substituents may optionally be joined to form a substituted orunsubstituted 6 membered heteroaryl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form a substituted 5 to 6membered heteroaryl. In embodiments, R⁴ and R⁹ substituents mayoptionally be joined to form a substituted 5 membered heteroaryl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form asubstituted 6 membered heteroaryl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form an unsubstituted 5 to 6membered heteroaryl. In embodiments, R⁴ and R⁹ substituents mayoptionally be joined to form an unsubstituted 5 membered heteroaryl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anunsubstituted 6 membered heteroaryl.

In embodiments, R⁴ and R⁹ substituents may optionally be joined to forman R⁴-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁴-substituted or unsubstituted 5 membered heteroaryl. In embodiments,R⁴ and R⁹ substituents may optionally be joined to form anR³⁴-substituted or unsubstituted 6 membered heteroaryl. In embodiments,R⁴ and R⁹ substituents may optionally be joined to form anR³⁴-substituted 5 to 6 membered heteroaryl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form an R³⁴-substituted 5membered heteroaryl. In embodiments, R⁴ and R⁹ substituents mayoptionally be joined to form an R³⁴-substituted 6 membered heteroaryl.

In embodiments, R⁴ and R⁹ substituents may optionally be joined to forman R³⁹-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁴ and R⁹ substituents may optionally be joined to form anR³⁹-substituted or unsubstituted 5 membered heteroaryl. In embodiments,R⁴ and R⁹ substituents may optionally be joined to form anR³⁹-substituted or unsubstituted 6 membered heteroaryl. In embodiments,R⁴ and R⁹ substituents may optionally be joined to form anR³⁹-substituted 5 to 6 membered heteroaryl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form an R³⁹-substituted 5membered heteroaryl. In embodiments, R⁴ and R⁹ substituents mayoptionally be joined to form an R³⁹-substituted 6 membered heteroaryl.

In embodiments, R⁴ and R⁹ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl. In embodiments, R⁴and R⁹ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group)heterocycloalkyl. In embodiments, R⁴ and R⁹ substituents bonded to thesame nitrogen atom may optionally be joined to form an unsubstitutedheterocycloalkyl. In embodiments, R⁴ and R⁹ substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R⁴ and R⁹ substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).In embodiments, R⁴ and R⁹ substituents bonded to the same nitrogen atommay optionally be joined to form an unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered).

In embodiments, R⁴ and R⁹ substituents may optionally be joined to formsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroaryl. In embodiments, R⁴ and R⁹ substituents may optionally bejoined to form substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group)heteroaryl. In embodiments, R⁴ and R⁹ substituents may optionally bejoined to form an unsubstituted heteroaryl. In embodiments, R⁴ and R⁹substituents may optionally be joined to form substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R⁴ and R⁹ substituents may optionally bejoined to form substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). In embodiments, R⁴ and R⁹ substituentsmay optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁷ and R¹⁰ substituents may optionally be joined to forma substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orsubstituted or unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁷ and R¹⁰ substituents may optionally be joined to forma substituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted or unsubstituted 4 to 7 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted or unsubstituted 4 to 6 membered heterocycloalkyl.

In embodiments, R⁷ and R¹⁰ substituents may optionally be joined to forma substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted 3 membered heterocycloalkyl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form a substituted 4 memberedheterocycloalkyl. In embodiments, R⁷ and R¹⁰ substituents may optionallybe joined to form a substituted 5 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted 6 membered heterocycloalkyl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form a substituted 7 memberedheterocycloalkyl. In embodiments, R⁷ and R¹⁰ substituents may optionallybe joined to form a substituted 8 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anunsubstituted 3 membered heterocycloalkyl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form an unsubstituted 4membered heterocycloalkyl. In embodiments, R⁷ and R¹⁰ substituents mayoptionally be joined to form an unsubstituted 5 memberedheterocycloalkyl. In embodiments, R⁷ and R¹⁰ substituents may optionallybe joined to form an unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anunsubstituted 7 membered heterocycloalkyl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form an unsubstituted 8membered heterocycloalkyl.

In embodiments, R⁷ and R¹⁰ substituents may optionally be joined to forman R³⁷-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orR³⁷-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR³⁷-substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR³⁷-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR³⁷-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR³⁷-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR³⁷-substituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR³⁷-substituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR³⁷-substituted 3 membered heterocycloalkyl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form an R³⁷-substituted 4membered heterocycloalkyl. In embodiments, R⁷ and R¹⁰ substituents mayoptionally be joined to form an R³⁷-substituted 5 memberedheterocycloalkyl. In embodiments, R⁷ and R¹⁰ substituents may optionallybe joined to form an R³⁷-substituted 6 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR³⁷-substituted 7 membered heterocycloalkyl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form an R³⁷-substituted 8membered heterocycloalkyl.

In embodiments, R⁷ and R¹⁰ substituents may optionally be joined to forman R⁴⁰-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orR⁴⁰-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR⁴⁰-substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR⁴⁰-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR⁴⁰-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR⁴⁰-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR⁴⁰-substituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR⁴⁰-substituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR⁴⁰-substituted 3 membered heterocycloalkyl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form an R⁴⁰-substituted 4membered heterocycloalkyl. In embodiments, R⁷ and R¹⁰ substituents mayoptionally be joined to form an R⁴⁰-substituted 5 memberedheterocycloalkyl. In embodiments, R⁷ and R¹⁰ substituents may optionallybe joined to form an R⁴⁰-substituted 6 membered heterocycloalkyl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR⁴⁰-substituted 7 membered heterocycloalkyl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form an R⁴⁰-substituted 8membered heterocycloalkyl.

In embodiments, R⁷ and R¹⁰ substituents may optionally be joined to forma substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted or unsubstituted 5 membered heteroaryl. In embodiments, R⁷and R¹⁰ substituents may optionally be joined to form a substituted orunsubstituted 6 membered heteroaryl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form a substituted 5 to 6membered heteroaryl. In embodiments, R⁷ and R¹⁰ substituents mayoptionally be joined to form a substituted 5 membered heteroaryl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted 6 membered heteroaryl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form an unsubstituted 5 to 6membered heteroaryl. In embodiments, R⁷ and R¹⁰ substituents mayoptionally be joined to form an unsubstituted 5 membered heteroaryl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anunsubstituted 6 membered heteroaryl.

In embodiments, R⁷ and R¹⁰ substituents may optionally be joined to forman R³⁷-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR³⁷-substituted or unsubstituted 5 membered heteroaryl. In embodiments,R⁷ and R¹⁰ substituents may optionally be joined to form anR³⁷-substituted or unsubstituted 6 membered heteroaryl. In embodiments,R⁷ and R¹⁰ substituents may optionally be joined to form anR³⁷-substituted 5 to 6 membered heteroaryl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form an R³⁷-substituted 5membered heteroaryl. In embodiments, R⁷ and R¹⁰ substituents mayoptionally be joined to form an R³⁷-substituted 6 membered heteroaryl.

In embodiments, R⁷ and R¹⁰ substituents may optionally be joined to forman R⁴⁰-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁷ and R¹⁰ substituents may optionally be joined to form anR⁴⁰-substituted or unsubstituted 5 membered heteroaryl. In embodiments,R⁷ and R¹⁰ substituents may optionally be joined to form anR⁴⁰-substituted or unsubstituted 6 membered heteroaryl. In embodiments,R⁷ and R¹⁰ substituents may optionally be joined to form anR⁴⁰-substituted 5 to 6 membered heteroaryl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form an R⁴⁰-substituted 5membered heteroaryl. In embodiments, R⁷ and R¹⁰ substituents mayoptionally be joined to form an R⁴⁰-substituted 6 membered heteroaryl.

In embodiments, R⁷ and R¹⁰ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl. In embodiments, R⁷and R¹⁰ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group)heterocycloalkyl. In embodiments, R⁷ and R¹⁰ substituents bonded to thesame nitrogen atom may optionally be joined to form an unsubstitutedheterocycloalkyl. In embodiments, R⁷ and R¹⁰ substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R⁷ and R¹⁰ substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).In embodiments, R⁷ and R¹⁰ substituents bonded to the same nitrogen atommay optionally be joined to form an unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered).

In embodiments, R⁷ and R¹⁰ substituents may optionally be joined to formsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroaryl. In embodiments, R⁷ and R¹⁰ substituents may optionally bejoined to form substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group)heteroaryl. In embodiments, R⁷ and R¹⁰ substituents may optionally bejoined to form an unsubstituted heteroaryl. In embodiments, R⁷ and R¹⁰substituents may optionally be joined to form substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R⁷ and R¹⁰ substituents may optionallybe joined to form substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). In embodiments, R⁷ and R¹⁰ substituentsmay optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁵ and R¹¹ substituents may optionally be joined to forma substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orsubstituted or unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁵ and R¹¹ substituents may optionally be joined to forma substituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form asubstituted or unsubstituted 4 to 7 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form asubstituted or unsubstituted 4 to 6 membered heterocycloalkyl.

In embodiments, R⁵ and R¹¹ substituents may optionally be joined to forma substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form asubstituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form asubstituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form asubstituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form asubstituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form asubstituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form asubstituted 3 membered heterocycloalkyl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form a substituted 4 memberedheterocycloalkyl. In embodiments, R⁵ and R¹¹ substituents may optionallybe joined to form a substituted 5 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form asubstituted 6 membered heterocycloalkyl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form a substituted 7 memberedheterocycloalkyl. In embodiments, R⁵ and R¹¹ substituents may optionallybe joined to form a substituted 8 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anunsubstituted 3 membered heterocycloalkyl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form an unsubstituted 4membered heterocycloalkyl. In embodiments, R⁵ and R¹¹ substituents mayoptionally be joined to form an unsubstituted 5 memberedheterocycloalkyl. In embodiments, R⁵ and R¹¹ substituents may optionallybe joined to form an unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anunsubstituted 7 membered heterocycloalkyl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form an unsubstituted 8membered heterocycloalkyl.

In embodiments, R⁵ and R¹¹ substituents may optionally be joined to forman R⁵-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orR³⁵-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR³⁵-substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR³⁵-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR³⁵-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR³⁵-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR³⁵-substituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR³⁵-substituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR³⁵-substituted 3 membered heterocycloalkyl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form an R³⁵-substituted 4membered heterocycloalkyl. In embodiments, R⁵ and R¹¹ substituents mayoptionally be joined to form an R³⁵-substituted 5 memberedheterocycloalkyl. In embodiments, R⁵ and R¹¹ substituents may optionallybe joined to form an R³⁵-substituted 6 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR³⁵-substituted 7 membered heterocycloalkyl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form an R³⁵-substituted 8membered heterocycloalkyl.

In embodiments, R⁵ and R¹¹ substituents may optionally be joined to forman R⁴¹-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orR⁴¹-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR⁴¹-substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR⁴¹-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR⁴¹-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR⁴¹-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR⁴¹-substituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR⁴¹-substituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR⁴¹-substituted 3 membered heterocycloalkyl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form an R⁴¹-substituted 4membered heterocycloalkyl. In embodiments, R⁵ and R¹¹ substituents mayoptionally be joined to form an R⁴¹-substituted 5 memberedheterocycloalkyl. In embodiments, R⁵ and R¹¹ substituents may optionallybe joined to form an R⁴¹-substituted 6 membered heterocycloalkyl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR⁴¹-substituted 7 membered heterocycloalkyl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form an R⁴¹-substituted 8membered heterocycloalkyl.

In embodiments, R⁵ and R¹¹ substituents may optionally be joined to forma substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form asubstituted or unsubstituted 5 membered heteroaryl. In embodiments, R⁵and R¹¹ substituents may optionally be joined to form a substituted orunsubstituted 6 membered heteroaryl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form a substituted 5 to 6membered heteroaryl. In embodiments, R⁵ and R¹¹ substituents mayoptionally be joined to form a substituted 5 membered heteroaryl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form asubstituted 6 membered heteroaryl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form an unsubstituted 5 to 6membered heteroaryl. In embodiments, R⁵ and R¹¹ substituents mayoptionally be joined to form an unsubstituted 5 membered heteroaryl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anunsubstituted 6 membered heteroaryl.

In embodiments, R⁵ and R¹¹ substituents may optionally be joined to forman R³⁵-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR³⁵-substituted or unsubstituted 5 membered heteroaryl. In embodiments,R⁵ and R¹¹ substituents may optionally be joined to form anR³⁵-substituted or unsubstituted 6 membered heteroaryl. In embodiments,R⁵ and R¹¹ substituents may optionally be joined to form anR³⁵-substituted 5 to 6 membered heteroaryl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form an R³⁵-substituted 5membered heteroaryl. In embodiments, R⁵ and R¹¹ substituents mayoptionally be joined to form an R³⁵-substituted 6 membered heteroaryl.

In embodiments, R⁵ and R¹¹ substituents may optionally be joined to forman R⁴¹-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁵ and R¹¹ substituents may optionally be joined to form anR⁴¹-substituted or unsubstituted 5 membered heteroaryl. In embodiments,R⁵ and R¹¹ substituents may optionally be joined to form anR⁴¹-substituted or unsubstituted 6 membered heteroaryl. In embodiments,R⁵ and R¹¹ substituents may optionally be joined to form anR⁴¹-substituted 5 to 6 membered heteroaryl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form an R⁴¹-substituted 5membered heteroaryl. In embodiments, R⁵ and R¹¹ substituents mayoptionally be joined to form an R⁴¹-substituted 6 membered heteroaryl.

In embodiments, R⁵ and R¹¹ substituents bonded to the same nitrogen atommay optionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl. In embodiments, R⁵and R¹¹ substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group)heterocycloalkyl. In embodiments, R⁵ and R¹¹ substituents bonded to thesame nitrogen atom may optionally be joined to form an unsubstitutedheterocycloalkyl. In embodiments, R⁵ and R¹¹ substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R⁵ and R¹¹ substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).In embodiments, R⁵ and R¹¹ substituents bonded to the same nitrogen atommay optionally be joined to form an unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered).

In embodiments, R⁵ and R¹¹ substituents may optionally be joined to formsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroaryl. In embodiments, R⁵ and R¹¹ substituents may optionally bejoined to form substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group)heteroaryl. In embodiments, R⁵ and R¹¹ substituents may optionally bejoined to form an unsubstituted heteroaryl. In embodiments, R⁵ and R¹¹substituents may optionally be joined to form substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R⁵ and R¹¹ substituents may optionallybe joined to form substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). In embodiments, R⁵ and R¹¹ substituentsmay optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁶ and R¹² substituents may optionally be joined to forma substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orsubstituted or unsubstituted 5 to 6 membered heteroaryl.

In embodiments, R⁶ and R¹² substituents may optionally be joined to forma substituted or unsubstituted 3 to 8 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form asubstituted or unsubstituted 4 to 7 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form asubstituted or unsubstituted 4 to 6 membered heterocycloalkyl.

In embodiments, R⁶ and R¹² substituents may optionally be joined to forma substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form asubstituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form asubstituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form asubstituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form asubstituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form asubstituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form asubstituted 3 membered heterocycloalkyl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form a substituted 4 memberedheterocycloalkyl. In embodiments, R⁶ and R¹² substituents may optionallybe joined to form a substituted 5 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form asubstituted 6 membered heterocycloalkyl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form a substituted 7 memberedheterocycloalkyl. In embodiments, R⁶ and R¹² substituents may optionallybe joined to form a substituted 8 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anunsubstituted 3 membered heterocycloalkyl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form an unsubstituted 4membered heterocycloalkyl. In embodiments, R⁶ and R¹² substituents mayoptionally be joined to form an unsubstituted 5 memberedheterocycloalkyl. In embodiments, R⁶ and R¹² substituents may optionallybe joined to form an unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anunsubstituted 7 membered heterocycloalkyl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form an unsubstituted 8membered heterocycloalkyl.

In embodiments, R⁶ and R¹² substituents may optionally be joined to forman R³⁶-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orR³⁶-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR³⁶-substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR³⁶-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR³⁶-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR³⁶-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR³⁶-substituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR³⁶-substituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR³⁶-substituted 3 membered heterocycloalkyl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form an R³⁶-substituted 4membered heterocycloalkyl. In embodiments, R⁶ and R¹² substituents mayoptionally be joined to form an R³⁶-substituted 5 memberedheterocycloalkyl. In embodiments, R⁶ and R¹² substituents may optionallybe joined to form an R³⁶-substituted 6 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR³⁶-substituted 7 membered heterocycloalkyl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form an R³⁶-substituted 8membered heterocycloalkyl.

In embodiments, R⁶ and R¹² substituents may optionally be joined to forman R⁴²-substituted or unsubstituted 3 to 8 membered heterocycloalkyl, orR⁴²-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR⁴²-substituted or unsubstituted 3 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR⁴²-substituted or unsubstituted 4 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR⁴²-substituted or unsubstituted 5 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR⁴²-substituted or unsubstituted 6 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR⁴²-substituted or unsubstituted 7 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR⁴²-substituted or unsubstituted 8 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR⁴²-substituted 3 membered heterocycloalkyl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form an R⁴²-substituted 4membered heterocycloalkyl. In embodiments, R⁶ and R¹² substituents mayoptionally be joined to form an R⁴²-substituted 5 memberedheterocycloalkyl. In embodiments, R⁶ and R¹² substituents may optionallybe joined to form an R⁴²-substituted 6 membered heterocycloalkyl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR⁴²-substituted 7 membered heterocycloalkyl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form an R⁴²-substituted 8membered heterocycloalkyl.

In embodiments, R⁶ and R¹² substituents may optionally be joined to forma substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form asubstituted or unsubstituted 5 membered heteroaryl. In embodiments, R⁶and R¹² substituents may optionally be joined to form a substituted orunsubstituted 6 membered heteroaryl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form a substituted 5 to 6membered heteroaryl. In embodiments, R⁶ and R¹² substituents mayoptionally be joined to form a substituted 5 membered heteroaryl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form asubstituted 6 membered heteroaryl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form an unsubstituted 5 to 6membered heteroaryl. In embodiments, R⁶ and R¹² substituents mayoptionally be joined to form an unsubstituted 5 membered heteroaryl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anunsubstituted 6 membered heteroaryl.

In embodiments, R⁶ and R¹² substituents may optionally be joined to forman R³⁶-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR³⁶-substituted or unsubstituted 5 membered heteroaryl. In embodiments,R⁶ and R¹² substituents may optionally be joined to form anR³⁶-substituted or unsubstituted 6 membered heteroaryl. In embodiments,R⁶ and R¹² substituents may optionally be joined to form anR³⁶-substituted 5 to 6 membered heteroaryl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form an R³⁶-substituted 5membered heteroaryl. In embodiments, R⁶ and R¹² substituents mayoptionally be joined to form an R³⁶-substituted 6 membered heteroaryl.

In embodiments, R⁶ and R¹² substituents may optionally be joined to forman R⁴²-substituted or unsubstituted 5 to 6 membered heteroaryl. Inembodiments, R⁶ and R¹² substituents may optionally be joined to form anR⁴²-substituted or unsubstituted 5 membered heteroaryl. In embodiments,R⁶ and R¹² substituents may optionally be joined to form anR⁴²-substituted or unsubstituted 6 membered heteroaryl. In embodiments,R⁶ and R¹² substituents may optionally be joined to form anR⁴²-substituted 5 to 6 membered heteroaryl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form an R⁴²-substituted 5membered heteroaryl. In embodiments, R⁶ and R¹² substituents mayoptionally be joined to form an R⁴²-substituted 6 membered heteroaryl.

In embodiments, R⁶ and R¹² substituents bonded to the same nitrogen atommay optionally be joined to form a substituted (e.g., substituted with asubstituent group, a size-limited substituent group, or lowersubstituent group) or unsubstituted heterocycloalkyl. In embodiments, R⁶and R¹² substituents bonded to the same nitrogen atom may optionally bejoined to form a substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group)heterocycloalkyl. In embodiments, R⁶ and R¹² substituents bonded to thesame nitrogen atom may optionally be joined to form an unsubstitutedheterocycloalkyl. In embodiments, R⁶ and R¹² substituents bonded to thesame nitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered). In embodiments,R⁶ and R¹² substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted heterocycloalkyl (e.g., 3 to 8 membered,3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).In embodiments, R⁶ and R¹² substituents bonded to the same nitrogen atommay optionally be joined to form an unsubstituted heterocycloalkyl(e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5membered, or 5 to 6 membered).

In embodiments, R⁶ and R¹² substituents may optionally be joined to formsubstituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheteroaryl. In embodiments, R⁶ and R¹² substituents may optionally bejoined to form substituted (e.g., substituted with a substituent group,a size-limited substituent group, or lower substituent group)heteroaryl. In embodiments, R⁶ and R¹² substituents may optionally bejoined to form an unsubstituted heteroaryl. In embodiments, R⁶ and R¹²substituents may optionally be joined to form substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered). In embodiments, R⁶ and R¹² substituents may optionallybe joined to form substituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered). In embodiments, R⁶ and R¹² substituentsmay optionally be joined to form an unsubstituted heteroaryl (e.g., 5 to10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R⁸ is hydrogen or a bioconjugate reactive moiety. Inembodiments, R⁸ is hydrogen. In embodiments, R⁸ is —NH₂,

In embodiments, R⁸ is —NH₂,

In embodiments, R⁸ is —NH₂,

In embodiments, R⁸ is —NH₂. In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

In embodiments, R⁸ is

B is a divalent base.

R¹⁵ is independently hydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃,—CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —OH,—NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃,—OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered), a 5′-nucleoside protecting group, monophosphate moietyor derivative thereof (e.g., phosphoramidate moiety, phosphorothioatemoiety, phosphorodithioate moiety, or O-methylphosphoroamidite moiety),polyphosphate moiety or derivative thereof (e.g., including aphosphoramidate, phosphorothioate, phosphorodithioate, orO-methylphosphoroamidite), or nucleic acid moiety or derivative thereof(e.g., including a phosphoramidate, phosphorothioate,phosphorodithioate, or O-methylphosphoroamidite).

R¹⁶ and R¹⁷ are each independently hydrogen, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl(e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substituted or unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), substituted or unsubstitutedcycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), substituted orunsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered,4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted orunsubstituted aryl (e.g., C₆-C₁₀ or phenyl), substituted orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered); polyphosphate moiety or derivative thereof (e.g.,including a phosphoramidate, phosphorothioate, phosphorodithioate, orO-methylphosphoroamidite), nucleic acid moiety or derivative thereof(e.g., including a phosphoramidate, phosphorothioate,phosphorodithioate, or O-methylphosphoroamidite), apolymerase-compatible cleavable moiety, or an —O-polymerase-compatiblecleavable moiety.

In embodiments, B is a divalent cytosine or a derivative thereof,divalent guanine or a derivative thereof, divalent adenine or aderivative thereof, divalent thymine or a derivative thereof, divalenturacil or a derivative thereof, divalent hypoxanthine or a derivativethereof, divalent xanthine or a derivative thereof, divalent7-methylguanine or a derivative thereof, divalent 5,6-dihydrouracil or aderivative thereof, divalent 5-methylcytosine or a derivative thereof,or divalent 5-hydroxymethylcytosine or a derivative thereof.

In embodiments, B is a divalent cytosine or a derivative thereof. Inembodiments, B is a divalent guanine or a derivative thereof. Inembodiments, B is a divalent adenine or a derivative thereof. Inembodiments, B is a divalent thymine or a derivative thereof. Inembodiments, B is a divalent uracil or a derivative thereof. Inembodiments, B is a divalent hypoxanthine or a derivative thereof. Inembodiments, B is a divalent xanthine or a derivative thereof. Inembodiments, B is a divalent 7-methylguanine or a derivative thereof. Inembodiments, B is a divalent 5,6-dihydrouracil or a derivative thereof.In embodiments, B is a divalent 5-methylcytosine or a derivativethereof. In embodiments, B is a divalent 5-hydroxymethylcytosine or aderivative thereof.

In embodiments, B is a divalent cytosine. In embodiments, B is adivalent guanine. In embodiments, B is a divalent adenine. Inembodiments, B is a divalent thymine. In embodiments, B is a divalenturacil. In embodiments, B is a divalent hypoxanthine. In embodiments, Bis a divalent xanthine. In embodiments, B is a divalent 7-methylguanine.In embodiments, B is a divalent 5,6-dihydrouracil. In embodiments, B isa divalent 5-methylcytosine. In embodiments, B is a divalent5-hydroxymethylcytosine.

In embodiments, R¹⁵ is independently hydrogen, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, a5′-nucleoside protecting group, monophosphate moiety, polyphosphatemoiety, or nucleic acid moiety. In embodiments, R¹⁵ is independentlyhydrogen, halogen, —CCl₃, —CBr₃, —CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂,—CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I, —CN, —NH₂, —COOH, —CONH₂, —NO₂,—SH, —SO₃H, —SO₂NH₂, —NHNH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —N₃, —SF₅, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, R¹⁵ is a 5′-nucleoside protecting group. Inembodiments, R¹⁵ is a monophosphate moiety, polyphosphate moiety, ornucleic acid moiety. In embodiments, R¹⁵ is a monophosphate moiety. Inembodiments, R¹⁵ is a polyphosphate moiety. In embodiments, R¹⁵ is anucleic acid moiety. In embodiments, R¹⁵ is hydrogen. In embodiments,R¹⁵ is a triphosphate moiety. In embodiments, R¹⁵ is —OH.

In embodiments, R¹⁵ is independently a 5′-nucleoside protecting group;and the 5′-nucleoside protecting group is

wherein R¹⁸ is substituted or unsubstituted C₁-C₄ alkyl. R¹⁹ and R²⁰ areeach independently halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂,—CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I,—OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—N₃, substituted or unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, orC₁-C₂), substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered,2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered),substituted or unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6membered), substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl),or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to9 membered, or 5 to 6 membered). The symbols z19 and z20 are eachindependently integers from 0 to 5. In embodiments, z19 and z20 are 0.

In embodiments, R¹⁸ is independently substituted (e.g., substituted witha substituent group, a size-limited substituent group, or lowersubstituent group) C₁-C₄ alkyl. In embodiments, R¹⁸ is an unsubstitutedmethyl. In embodiments, R¹⁸ is an unsubstituted C₂ alkyl. Inembodiments, R¹⁸ is an unsubstituted C₃ alkyl. In embodiments, R¹⁸ is anunsubstituted C₄ alkyl. In embodiments, R¹⁸ is an unsubstitutedtert-butyl.

In embodiments, R¹⁸ is independently R⁴⁸-substituted or unsubstitutedC₁-C₄ alkyl.

In embodiments, R¹⁹ and R²⁰ are each independently substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted heteroalkyl, substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted cycloalkyl,substituted (e.g., substituted with a substituent group, a size-limitedsubstituent group, or lower substituent group) or unsubstitutedheterocycloalkyl, substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted aryl, or substituted (e.g., substituted with a substituentgroup, a size-limited substituent group, or lower substituent group) orunsubstituted heteroaryl. In embodiments, R¹⁹ and R²⁰ are eachindependently unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstitutedaryl, or unsubstituted heteroaryl.

In embodiments, R¹⁹ is independently halogen, —CF₃, —CCl₃, —CI₃, —CBr₃,—CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F,—OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃,—OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)OH, —NHOH, —N₃, R⁴⁹-substituted or unsubstitutedalkyl, R⁴⁹-substituted or unsubstituted heteroalkyl, R⁴⁹-substituted orunsubstituted cycloalkyl, R⁴⁹-substituted or unsubstitutedheterocycloalkyl, R⁴⁹-substituted or unsubstituted aryl, orR⁴⁹-substituted or unsubstituted heteroaryl.

In embodiments, R²⁰ is independently halogen, —CF₃, —CCl₃, —CI₃, —CBr₃,—CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F,—OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃,—OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)OH, —NHOH, —N₃, R⁵⁰-substituted or unsubstitutedalkyl, R⁵⁰-substituted or unsubstituted heteroalkyl, R⁵⁰-substituted orunsubstituted cycloalkyl, R⁵⁰-substituted or unsubstitutedheterocycloalkyl, R⁵⁰-substituted or unsubstituted aryl, orR⁵⁰-substituted or unsubstituted heteroaryl.

R⁴⁸, R⁴⁹, and R⁵⁰ are each independently oxo, halogen, —CF₃, —CCl₃,—CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —N₃, unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered).

In embodiments, R¹⁶ is independently hydrogen, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R¹⁶ is independently a polymerase-compatible cleavablemoiety. In embodiments, R¹⁶ is independently an —O-polymerase-compatiblecleavable moiety.

In embodiments, R¹⁶ is independently hydrogen, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁴⁶-substituted or unsubstitutedalkyl, R⁴⁶-substituted or unsubstituted heteroalkyl, R⁴⁶-substituted orunsubstituted cycloalkyl, R⁴⁶-substituted or unsubstitutedheterocycloalkyl, R⁴⁶-substituted or unsubstituted aryl, orR⁴⁶-substituted or unsubstituted heteroaryl.

In embodiments, R¹⁶ is hydrogen. In embodiments, R¹⁶ is —OH. Inembodiments, R¹⁶ is —O-polymerase-compatible cleavable moiety.

In embodiments, R¹⁶ is a polymerase-compatible cleavable moiety or an—O-polymerase-compatible cleavable moiety; and the polymerase-compatiblecleavable moiety is independently

In embodiments, the —O-polymerase cleavable moiety is a moiety describedin US 2018/0274024, which is incorporated herein in its entirety for allpurposes.

In embodiments, R¹⁷ is independently hydrogen, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, R¹⁷ is independently a polymerase-compatible cleavablemoiety. In embodiments, R¹⁷ is independently an —O-polymerase-compatiblecleavable moiety.

In embodiments, R¹⁷ is independently hydrogen, halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅, R⁴⁷-substituted or unsubstitutedalkyl, R⁴⁷-substituted or unsubstituted heteroalkyl, R⁴⁷-substituted orunsubstituted cycloalkyl, R⁴⁷-substituted or unsubstitutedheterocycloalkyl, R⁴⁷-substituted or unsubstituted aryl, orR⁴⁷-substituted or unsubstituted heteroaryl.

R⁴⁶ and R⁴⁷ are each independently oxo, halogen, —CF₃, —CCl₃, —CI₃,—CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H,—NHC(O)H, —NHC(O)OH, —NHOH, —OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂,—OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl, —OCH₂Br, —OCH₂I, —OCH₂F, —N₃, —SF₅,unsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstitutedheteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g.,C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆), unsubstituted heterocycloalkyl (e.g., 3to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5to 6 membered), unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orunsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5to 6 membered).

In embodiments, R¹⁷ is hydrogen. In embodiments, R¹⁷ is —OH. Inembodiments, R¹⁷ is —O-polymerase-compatible cleavable moiety.

In embodiments, R¹⁷ is a polymerase-compatible cleavable moiety or an—O-polymerase-compatible cleavable moiety; and the polymerase-compatiblecleavable moiety is independently

In embodiments, the polymerase-compatible cleavable moiety isindependently

In embodiments, the polymerase-compatible cleavable moiety isindependently

In embodiments, R⁹ is independently hydrogen, R³⁹-substituted orunsubstituted alkyl, or R³⁹-substituted or unsubstituted heteroalkyl. Inembodiments, R⁹ is hydrogen. In embodiments, R⁹ is substituted orunsubstituted C₁ alkyl. In embodiments, R⁹ is substituted orunsubstituted C₂ alkyl. In embodiments, R⁹ is substituted orunsubstituted C₃ alkyl. In embodiments, R⁹ is substituted orunsubstituted C₄ alkyl. In embodiments, R⁹ is substituted orunsubstituted C₅ alkyl. In embodiments, R⁹ is substituted orunsubstituted C₆ alkyl. In embodiments, R⁹ is substituted C₁ alkyl. Inembodiments, R⁹ is substituted C₂ alkyl. In embodiments, R⁹ issubstituted C₃ alkyl. In embodiments, R⁹ is substituted C₄ alkyl. Inembodiments, R⁹ is substituted C₅ alkyl. In embodiments, R⁹ issubstituted C₆ alkyl. In embodiments, R⁹ is unsubstituted C₁ alkyl. Inembodiments, R⁹ is unsubstituted C₂ alkyl. In embodiments, R⁹ isunsubstituted C₃ alkyl. In embodiments, R⁹ is unsubstituted C₄ alkyl. Inembodiments, R⁹ is unsubstituted C₅ alkyl. In embodiments, R⁹ isunsubstituted C₆ alkyl. In embodiments, R⁹ is R³⁹-substituted orunsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R³⁹ is independently—PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

In embodiments, R⁹ is independently hydrogen, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl, or substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl.

In embodiments, R¹⁰ is independently hydrogen, R⁴⁰-substituted orunsubstituted alkyl, or R⁴⁰-substituted or unsubstituted heteroalkyl. Inembodiments, R¹⁰ is hydrogen. In embodiments, R¹⁰ is substituted orunsubstituted C₁ alkyl. In embodiments, R¹⁰ is substituted orunsubstituted C₂ alkyl. In embodiments, R¹⁰ is substituted orunsubstituted C₃ alkyl. In embodiments, R¹⁰ is substituted orunsubstituted C₄ alkyl. In embodiments, R¹⁰ is substituted orunsubstituted C₅ alkyl. In embodiments, R¹⁰ is substituted orunsubstituted C₆ alkyl. In embodiments, R¹⁰ is substituted C₁ alkyl. Inembodiments, R¹⁰ is substituted C₂ alkyl. In embodiments, R¹⁰ issubstituted C₃ alkyl. In embodiments, R¹⁰ is substituted C₄ alkyl. Inembodiments, R¹⁰ is substituted C₅ alkyl. In embodiments, R¹⁰ issubstituted C₆ alkyl. In embodiments, R¹⁰ is unsubstituted C₁ alkyl. Inembodiments, R¹⁰ is unsubstituted C₂ alkyl. In embodiments, R¹⁰ isunsubstituted C₃ alkyl. In embodiments, R¹⁰ is unsubstituted C₄ alkyl.In embodiments, R¹⁰ is unsubstituted C₅ alkyl. In embodiments, R¹⁰ isunsubstituted C₆ alkyl. In embodiments, R¹⁰ is R⁴⁰-substituted orunsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R⁴⁰ is independently—PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

In embodiments, R¹⁰ is independently hydrogen, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl, or substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl.

In embodiments, R¹¹ is independently hydrogen, R⁴¹-substituted orunsubstituted alkyl, or R⁴¹-substituted or unsubstituted heteroalkyl. Inembodiments, R¹¹ is hydrogen. In embodiments, R¹¹ is substituted orunsubstituted C₁ alkyl. In embodiments, R¹¹ is substituted orunsubstituted C₂ alkyl. In embodiments, R¹¹ is substituted orunsubstituted C₃ alkyl. In embodiments, R¹¹ is substituted orunsubstituted C₄ alkyl. In embodiments, R¹¹ is substituted orunsubstituted C₅ alkyl. In embodiments, R¹¹ is substituted orunsubstituted C₆ alkyl. In embodiments, R¹¹ is substituted C₁ alkyl. Inembodiments, R¹¹ is substituted C₂ alkyl. In embodiments, R¹¹ issubstituted C₃ alkyl. In embodiments, R¹¹ is substituted C₄ alkyl. Inembodiments, R¹¹ is substituted C₅ alkyl. In embodiments, R¹¹ issubstituted C₆ alkyl. In embodiments, R¹¹ is unsubstituted C₁ alkyl. Inembodiments, R¹¹ is unsubstituted C₂ alkyl. In embodiments, R¹¹ isunsubstituted C₃ alkyl. In embodiments, R¹¹ is unsubstituted C₄ alkyl.In embodiments, R¹¹ is unsubstituted C₅ alkyl. In embodiments, R¹¹ isunsubstituted C₆ alkyl. In embodiments, R¹¹ is R⁴¹-substituted orunsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R⁴¹ is independently—PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

In embodiments, R¹¹ is independently hydrogen, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl, or substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl.

In embodiments, R¹² is independently hydrogen, R⁴²-substituted orunsubstituted alkyl, or R⁴²-substituted or unsubstituted heteroalkyl. Inembodiments, R¹² is hydrogen. In embodiments, R¹² is substituted orunsubstituted C₁ alkyl. In embodiments, R¹² is substituted orunsubstituted C₂ alkyl. In embodiments, R¹² is substituted orunsubstituted C₃ alkyl. In embodiments, R¹² is substituted orunsubstituted C₄ alkyl. In embodiments, R¹² is substituted orunsubstituted C₅ alkyl. In embodiments, R¹² is substituted orunsubstituted C₆ alkyl. In embodiments, R¹² is substituted C₁ alkyl. Inembodiments, R¹² is substituted C₂ alkyl. In embodiments, R¹² issubstituted C₃ alkyl. In embodiments, R¹² is substituted C₄ alkyl. Inembodiments, R¹² is substituted C₅ alkyl. In embodiments, R¹² issubstituted C₆ alkyl. In embodiments, R¹² is unsubstituted C₁ alkyl. Inembodiments, R¹² is unsubstituted C₂ alkyl. In embodiments, R¹² isunsubstituted C₃ alkyl. In embodiments, R¹² is unsubstituted C₄ alkyl.In embodiments, R¹² is unsubstituted C₅ alkyl. In embodiments, R¹² isunsubstituted C₆ alkyl. In embodiments, R¹² is R⁴²-substituted orunsubstituted alkyl (e.g., C₁-C₆ alkyl), wherein R⁴² is independently—PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

In embodiments, R¹² is independently hydrogen, substituted (e.g.,substituted with a substituent group, a size-limited substituent group,or lower substituent group) or unsubstituted alkyl, or substituted(e.g., substituted with a substituent group, a size-limited substituentgroup, or lower substituent group) or unsubstituted heteroalkyl.

R³⁹, R⁴⁰, R⁴¹, and R⁴² are each independently halogen, —CCl₃, —CBr₃,—CF₃, —CI₃, —CHCl₂, —CHBr₂, —CHF₂, —CHI₂, —CH₂Cl, —CH₂Br, —CH₂F, —CH₂I,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC(O)NHNH₂, —NHC(O)NH₂, —NHSO₂H, —NHC(O)H, —NHC(O)OH, —NHOH,—OCCl₃, —OCF₃, —OCBr₃, —OCI₃, —OCHCl₂, —OCHBr₂, —OCHI₂, —OCHF₂, —OCH₂Cl,—OCH₂Br, —OCH₂I, —OCH₂F, —PO₄H, —PO₃H, —N₃, unsubstituted alkyl (e.g.,C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), unsubstituted heteroalkyl (e.g., 2 to 8membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5membered), unsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, orC₅-C₆), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), or unsubstituted heteroaryl(e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Inembodiments, R³⁹, R⁴⁰, R⁴¹, and R⁴² are each independently —PO₃H, —PO₄H,—SO₂NH₂, —SO₃H, or —SO₄H. In embodiments, R³⁹, R⁴⁰, R⁴¹, and R⁴² areeach independently —SO₃H. In embodiments, R³⁹, R⁴⁰, R⁴¹, and R⁴² areeach independently —PO₃H. In embodiments, R³⁹, R⁴⁰, R⁴¹, and R⁴² areeach independently —SO₂NH₂. In embodiments, R³⁹, R⁴⁰, R⁴¹, and R⁴² areeach independently —SO₄H.

In embodiments, the compound has the formula:

wherein R⁴, R⁵, R⁹, R¹¹, R¹², R⁶, R⁷, R¹⁰, R¹, L¹, L², and R⁸ are asdescribed herein, including embodiments.

In embodiments, the compound has the formula:

wherein R⁹, R¹¹, R¹², R¹⁰, R¹, L¹, L², and R⁸ are as described herein,including embodiments.

In embodiments, the compound has the formula:

wherein R⁴, R⁵, R⁹, R¹¹, R², R³, R¹², R⁶, R⁷, R¹⁰, and R⁸ are asdescribed herein, including embodiments.

In embodiments, the compound has the formula:

wherein R⁵, R⁶, R², R³, R¹, L¹, L², and R⁸ are as described herein,including embodiments. R²³ and R²⁴ are independently a substituentgroup, a size-limited substituent group, or lower substituent group. Thesymbols z23 and z24 are independently integers from 0 to 6.

In embodiments, R²³ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃,—CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, R²⁴ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃,—CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, R²⁴ is substituted or unsubstituted C₁ alkyl. Inembodiments, R²⁴ is substituted or unsubstituted C₂ alkyl. Inembodiments, R²⁴ is substituted or unsubstituted C₃ alkyl. Inembodiments, R²⁴ is substituted or unsubstituted C₄ alkyl. Inembodiments, R²⁴ is substituted or unsubstituted C₅ alkyl. Inembodiments, R²⁴ is substituted or unsubstituted C₆ alkyl. Inembodiments, R²⁴ is substituted C₁ alkyl. In embodiments, R²⁴ issubstituted C₂ alkyl. In embodiments, R²⁴ is substituted C₃ alkyl. Inembodiments, R²⁴ is substituted C₄ alkyl. In embodiments, R²⁴ issubstituted C₅ alkyl. In embodiments, R²⁴ is substituted C₆ alkyl. Inembodiments, R²⁴ is unsubstituted C₁ alkyl. In embodiments, R²⁴ isunsubstituted C₂ alkyl. In embodiments, R²⁴ is unsubstituted C₃ alkyl.In embodiments, R²⁴ is unsubstituted C₄ alkyl. In embodiments, R²⁴ isunsubstituted C₅ alkyl. In embodiments, R²⁴ is unsubstituted C₆ alkyl.In embodiments, R²⁴ is a substituted or unsubstituted alkyl (e.g., C₁-C₆alkyl), wherein R²⁴ is independently substituted with a substituentgroup selected from —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H. Inembodiments, R²³ is substituted or unsubstituted C₁ alkyl. Inembodiments, R²³ is substituted or unsubstituted C₂ alkyl. Inembodiments, R²³ is substituted or unsubstituted C₃ alkyl. Inembodiments, R²³ is substituted or unsubstituted C₄ alkyl. Inembodiments, R²³ is substituted or unsubstituted C₅ alkyl. Inembodiments, R²³ is substituted or unsubstituted C₆ alkyl. Inembodiments, R²³ is substituted C₁ alkyl. In embodiments, R²³ issubstituted C₂ alkyl. In embodiments, R²³ is substituted C₃ alkyl. Inembodiments, R²³ is substituted C₄ alkyl. In embodiments, R²³ issubstituted C₅ alkyl. In embodiments, R²³ is substituted C₆ alkyl. Inembodiments, R²³ is unsubstituted C₁ alkyl. In embodiments, R²³ isunsubstituted C₂ alkyl. In embodiments, R²³ is unsubstituted C₃ alkyl.In embodiments, R²³ is unsubstituted C₄ alkyl. In embodiments, R²³ isunsubstituted C₅ alkyl. In embodiments, R²³ is unsubstituted C₆ alkyl.In embodiments, R²³ is a substituted or unsubstituted alkyl (e.g., C₁-C₆alkyl), wherein R²³ is independently substituted with a substituentgroup selected from —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

In embodiments, the compound has the formula:

wherein R⁵, R¹¹, R¹², R², R³, R⁶, R¹, L¹, L² and R⁸ are as describedherein, including embodiments. R²³ and R²⁴ are independently asubstituent group, a size-limited substituent group, or lowersubstituent group. The symbols z23 and z24 are independently integersfrom 0 to 6. In embodiments, z23 is 0. In embodiments, z23 is 1. Inembodiments, z23 is 2. In embodiments, z23 is 3. In embodiments, z23 is4. In embodiments, z23 is 5. In embodiments, z23 is 6. In embodiments,z24 is 0. In embodiments, z24 is 1. In embodiments, z24 is 2. Inembodiments, z24 is 3. In embodiments, z24 is 4. In embodiments, z24 is5. In embodiments, z24 is 6.

In embodiments, the compound has the formula:

wherein R², R³, R¹, L¹, L², and R⁸ are as described herein, includingembodiments. R²³, R²⁴, R²⁵, and R²⁶ are independently a substituentgroup, a size-limited substituent group, or lower substituent group. Thesymbols z23, z24, z25, and z26 are independently integers from 0 to 6.In embodiments, z25 is 0. In embodiments, z25 is 1. In embodiments, z25is 2. In embodiments, z25 is 3. In embodiments, z25 is 4. Inembodiments, z25 is 5. In embodiments, z25 is 6. In embodiments, z26 is0. In embodiments, z26 is 1. In embodiments, z26 is 2. In embodiments,z26 is 3. In embodiments, z26 is 4. In embodiments, z26 is 5. Inembodiments, z26 is 6.

In embodiments, R²⁵ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃,—CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, R²⁶ is independently oxo, halogen, —CF₃, —CCl₃, —CI₃,—CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br,—OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂,—OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,—SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂,—NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃, substituted orunsubstituted alkyl (e.g., C₁-C₈, C₁-C₆, C₁-C₄, or C₁-C₂), substitutedor unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted orunsubstituted cycloalkyl (e.g., C₃-C₈, C₃-C₆, C₄-C₆, or C₅-C₆),substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered),substituted or unsubstituted aryl (e.g., C₆-C₁₀ or phenyl), orsubstituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9membered, or 5 to 6 membered).

In embodiments, R²⁵ is substituted or unsubstituted C₁ alkyl. Inembodiments, R²⁵ is substituted or unsubstituted C₂ alkyl. Inembodiments, R²⁵ is substituted or unsubstituted C₃ alkyl. Inembodiments, R²⁵ is substituted or unsubstituted C₄ alkyl. Inembodiments, R²⁵ is substituted or unsubstituted C₅ alkyl. Inembodiments, R²⁵ is substituted or unsubstituted C₆ alkyl. Inembodiments, R²⁵ is substituted C₁ alkyl. In embodiments, R²⁵ issubstituted C₂ alkyl. In embodiments, R²⁵ is substituted C₃ alkyl. Inembodiments, R²⁵ is substituted C₄ alkyl. In embodiments, R²⁵ issubstituted C₅ alkyl. In embodiments, R²⁵ is substituted C₆ alkyl. Inembodiments, R²⁵ is unsubstituted C₁ alkyl. In embodiments, R²⁵ isunsubstituted C₂ alkyl. In embodiments, R²⁵ is unsubstituted C₃ alkyl.In embodiments, R²⁵ is unsubstituted C₄ alkyl. In embodiments, R²⁵ isunsubstituted C₅ alkyl. In embodiments, R²⁵ is unsubstituted C₆ alkyl.In embodiments, R²⁵ is a substituted or unsubstituted alkyl (e.g., C₁-C₆alkyl), wherein R²⁵ is independently substituted with a substituentgroup selected from —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H. Inembodiments, R²⁶ is substituted or unsubstituted C₁ alkyl. Inembodiments, R²⁶ is substituted or unsubstituted C₂ alkyl. Inembodiments, R²⁶ is substituted or unsubstituted C₃ alkyl. Inembodiments, R²⁶ is substituted or unsubstituted C₄ alkyl. Inembodiments, R²⁶ is substituted or unsubstituted C₅ alkyl. Inembodiments, R²⁶ is substituted or unsubstituted C₆ alkyl. Inembodiments, R²⁶ is substituted C₁ alkyl. In embodiments, R²⁶ issubstituted C₂ alkyl. In embodiments, R²⁶ is substituted C₃ alkyl. Inembodiments, R²⁶ is substituted C₄ alkyl. In embodiments, R²⁶ issubstituted C₅ alkyl. In embodiments, R²⁶ is substituted C₆ alkyl. Inembodiments, R²⁶ is unsubstituted C₁ alkyl. In embodiments, R²⁶ isunsubstituted C₂ alkyl. In embodiments, R²⁶ is unsubstituted C₃ alkyl.In embodiments, R²⁶ is unsubstituted C₄ alkyl. In embodiments, R²⁶ isunsubstituted C₅ alkyl. In embodiments, R²⁶ is unsubstituted C₆ alkyl.In embodiments, R²⁶ is a substituted or unsubstituted alkyl (e.g., C₁-C₆alkyl), wherein R²⁶ is independently substituted with a substituentgroup selected from —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

In embodiments, the compound has the formula:

wherein R², R³, R⁵, R¹¹, R¹², R⁶, R¹, L¹, L², and R⁸ are as describedherein, including embodiments. R²³ and R²⁴ are independently asubstituent group, a size-limited substituent group, or lowersubstituent group. The symbols z23 and z24 are independently integersfrom 0 to 6. In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R¹, L¹, L², and R⁸ are as described herein,including embodiments. In embodiments, the compound has the formula:

wherein R¹, L¹, L², and R⁸ are as described herein, includingembodiments. In embodiments, the compound has the formula:

wherein L¹, L² and R⁸ are as described herein, including embodiments. Inembodiments, the compound has the formula:

Wherein R⁸ is as described herein, including embodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, R¹⁰, L¹, R¹, L², and R⁸ are as describedherein, including embodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, R¹⁰, L¹, R¹, L², and R⁸ are as describedherein, including embodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, R¹⁰, L¹, R¹, L², and R⁸ are as describedherein, including embodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, R¹⁰, L¹, R¹, L², and R⁸ are as describedherein, including embodiments.

In embodiments, the compound has the formula:

wherein R⁵, R⁶, R², R³, L¹, L², and R⁸ are as described herein,including embodiments; and L³ is independently

and R¹ is as described herein, including in embodiments. R²³ and R²⁴ areindependently a substituent group, a size-limited substituent group, orlower substituent group. The symbols z23 and z24 are independentlyintegers from 0 to 6.

In embodiments, the compound has the formula:

wherein R⁵, R¹¹, R¹², R², R³, R⁶, L¹, L², and R⁸ are as describedherein, including embodiments; and L³ is independently

and R¹ is as described herein, including in embodiments. R²³ and R²⁴ areindependently a substituent group, a size-limited substituent group, orlower substituent group. The symbols z23 and z24 are independentlyintegers from 0 to 6. In embodiments, z23 is 0. In embodiments, z23is 1. In embodiments, z23 is 2. In embodiments, z23 is 3. Inembodiments, z23 is 4. In embodiments, z23 is 5. In embodiments, z23 is6. In embodiments, z24 is 0. In embodiments, z24 is 1. In embodiments,z24 is 2. In embodiments, z24 is 3. In embodiments, z24 is 4. Inembodiments, z24 is 5. In embodiments, z24 is 6.

In embodiments, the compound has the formula:

wherein R², R³, L¹, L², and R⁸ are as described herein, includingembodiments; and L³ is independently

and R¹ is as described herein, including in embodiments. R²³, R²⁴, R²⁵,and R²⁶ are independently a substituent group, a size-limitedsubstituent group, or lower substituent group. The symbols z23, z24,z25, and z26 are independently integers from 0 to 6. In embodiments, z25is 0. In embodiments, z25 is 1. In embodiments, z25 is 2. Inembodiments, z25 is 3. In embodiments, z25 is 4. In embodiments, z25 is5. In embodiments, z25 is 6. In embodiments, z26 is 0. In embodiments,z26 is 1. In embodiments, z26 is 2. In embodiments, z26 is 3. Inembodiments, z26 is 4. In embodiments, z26 is 5. In embodiments, z26 is6.

In embodiments, the compound has the formula:

wherein R², R³, R⁵, R¹¹, R¹², L¹, L², and R⁸ are as described herein,including embodiments; and L³ is independently

and R¹ is as described herein, including in embodiments. R²³ and R²⁴ areindependently a substituent group, a size-limited substituent group, orlower substituent group. The symbols z23 and z24 are independentlyintegers from 0 to 6. In embodiments, z23 is 1. In embodiments, z24is 1. In embodiments, R²⁴ is substituted or unsubstituted C₁ alkyl. Inembodiments, R²⁴ is substituted or unsubstituted C₂ alkyl. Inembodiments, R²⁴ is substituted or unsubstituted C₃ alkyl. Inembodiments, R²⁴ is substituted or unsubstituted C₄ alkyl. Inembodiments, R²⁴ is substituted or unsubstituted C₅ alkyl. Inembodiments, R²⁴ is substituted or unsubstituted C₆ alkyl. Inembodiments, R²⁴ is substituted C₁ alkyl. In embodiments, R²⁴ issubstituted C₂ alkyl. In embodiments, R²⁴ is substituted C₃ alkyl. Inembodiments, R²⁴ is substituted C₄ alkyl. In embodiments, R²⁴ issubstituted C₅ alkyl. In embodiments, R²⁴ is substituted C₆ alkyl. Inembodiments, R²⁴ is unsubstituted C₁ alkyl. In embodiments, R²⁴ isunsubstituted C₂ alkyl. In embodiments, R²⁴ is unsubstituted C₃ alkyl.In embodiments, R²⁴ is unsubstituted C₄ alkyl. In embodiments, R²⁴ isunsubstituted C₅ alkyl. In embodiments, R²⁴ is unsubstituted C₆ alkyl.In embodiments, R²⁴ is a substituted or unsubstituted alkyl (e.g., C₁-C₆alkyl), wherein R²⁴ is independently substituted with a substituentgroup selected from —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H. Inembodiments, R²³ is substituted or unsubstituted C₁ alkyl. Inembodiments, R²³ is substituted or unsubstituted C₂ alkyl. Inembodiments, R²³ is substituted or unsubstituted C₃ alkyl. Inembodiments, R²³ is substituted or unsubstituted C₄ alkyl. Inembodiments, R²³ is substituted or unsubstituted C₅ alkyl. Inembodiments, R²³ is substituted or unsubstituted C₆ alkyl. Inembodiments, R²³ is substituted C₁ alkyl. In embodiments, R²³ issubstituted C₂ alkyl. In embodiments, R²³ is substituted C₃ alkyl. Inembodiments, R²³ is substituted C₄ alkyl. In embodiments, R²³ issubstituted C₅ alkyl. In embodiments, R²³ is substituted C₆ alkyl. Inembodiments, R²³ is unsubstituted C₁ alkyl. In embodiments, R²³ isunsubstituted C₂ alkyl. In embodiments, R²³ is unsubstituted C₃ alkyl.In embodiments, R²³ is unsubstituted C₄ alkyl. In embodiments, R²³ isunsubstituted C₅ alkyl. In embodiments, R²³ is unsubstituted C₆ alkyl.In embodiments, R²³ is a substituted or unsubstituted alkyl (e.g., C₁-C₆alkyl), wherein R²³ is independently substituted with a substituentgroup selected from —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², L¹, L², and R⁸ are as described herein,including embodiments; and L³ is independently

and R¹ is as described herein, including in embodiments. R²³ and R²⁴ areindependently a substituent group, a size-limited substituent group, orlower substituent group. The symbols z23 and z24 are independentlyintegers from 0 to 6. In embodiments, z23 is 0. In embodiments, z23is 1. In embodiments, z23 is 2. In embodiments, z23 is 3. Inembodiments, z23 is 4. In embodiments, z23 is 5. In embodiments, z23 is6. In embodiments, z24 is 0. In embodiments, z24 is 1. In embodiments,z24 is 2. In embodiments, z24 is 3. In embodiments, z24 is 4. Inembodiments, z24 is 5. In embodiments, z24 is 6.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, R¹⁰, L¹, L², and R⁸ are as describedherein, including embodiments; and L³ is independently

and R¹ is as described herein, including in embodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, R¹⁰, L¹, L², and R⁸ are as describedherein, including embodiments; and L³ is independently

and R¹ is as described herein, including in embodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, R¹⁰, L¹, L², and R⁸ are as describedherein, including embodiments; and L³ is independently

and R¹ is as described herein, including in embodiments.

In embodiments, the compound has the formula:

wherein R¹, L¹, L², R², R³, R⁴, R⁵, R⁶, R⁹, R¹¹, R¹², R⁸, R²⁴ and z24are as described herein. In embodiments, the compound has the formula:

wherein R¹, L¹, L², R², R³, R⁴, R⁶, R⁹, R¹¹, R¹², R⁸, R²⁴ and z24 are asdescribed herein. In embodiments the compound has the formula:

wherein R¹, L¹, L², R², R³, R⁶, R⁹, R¹¹, R¹², R⁸, R²⁴ and z24 are asdescribed herein. In embodiments, the compound has the formula:

wherein R¹, L¹, L², R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, and R⁸ are as describedherein. In embodiments, the compound has the formula:

wherein R¹, L¹, L², R⁴, R⁵, R⁶, R⁷, R⁹, and R⁸ are as described herein.In embodiments, the compound has the formula:

wherein R¹, L¹, L², R⁴, R⁵, R⁶, R⁷, and R⁸ are as described herein. Inembodiments, the compound has the formula:

wherein R¹, L¹, L², R⁹, and R⁸ are as described herein. In embodiments,the compound has the formula:

wherein R¹, L¹, L², R⁹, and R⁸ are as described herein. In embodiments,the compound has the formula:

wherein R¹, L¹, L², R², R³, and R⁸ are as described herein. Inembodiments, the compound has the formula:

wherein R², R³, R⁴, R⁵, R⁶, R⁹, R¹¹, R¹², R²⁴, and z24 are as describedherein.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, R¹⁰, and R⁸ are as described herein,including embodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, R¹⁰, and R⁸ are as described herein,including embodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, R¹⁰, and R⁸ are as described herein,including embodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, and R¹⁰ are as described herein, includingembodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, and R¹⁰ are as described herein, includingembodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, and R¹⁰ are as described herein, includingembodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, and R¹⁰ are as described herein, includingembodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, and R¹⁰ are as described herein, includingembodiments.

In embodiments, the compound has the formula:

wherein R², R³, R¹¹, R¹², R⁹, and R¹⁰ are as described herein, includingembodiments.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

wherein L³, L¹, L², and R⁸ are as described herein, includingembodiments.

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has the formula:

In embodiments, the compound has a maximum excitation of about 500 nm toabout 700 nm. In embodiments, the compound has a maximum excitation ofabout 600 nm to about 700 nm. In embodiments, the compound has a maximumexcitation of about 620 nm to about 700 nm. In embodiments, the compoundhas a maximum excitation of about 630 nm to about 700 nm. Inembodiments, the compound has a maximum excitation of about 630 nm toabout 670 nm. In embodiments, the compound has a maximum excitation ofabout 630 nm to about 660 nm. In embodiments, the compound is excited atabout 510 nm to about 650 nm. In embodiments, the compound is excited atabout 520 nm. In embodiments, the compound is excited at about 637 nm.

In embodiments, the compound has a maximum excitation of about 630 nm,631 nm, 632 nm, 633 nm, 634 nm, 635 nm, 636 nm, 637 nm, 638 nm, 639 nm,640 nm, 641 nm, 642 nm, 643 nm, 644 nm, 645 nm, 646 nm, 647 nm, 648 nm,649 nm, 650 nm, 651 nm, 652 nm, 653 nm, 654 nm, 655 nm, 656 nm, 657 nm,658 nm, 659 nm, 660 nm, 661 nm, 662 nm, 663 nm, 664 nm, 665 nm, 666 nm,667 nm, 668 nm, 669 nm, or about 670 nm.

In embodiments, the compound has a maximum emission of about 500 nm toabout 800 nm. In embodiments, the compound has a maximum emission ofabout 500 nm to about 700 nm. In embodiments, the compound has a maximumemission of about 600 nm to about 700 nm. In embodiments, the compoundhas a maximum emission of about 620 nm to about 700 nm. In embodiments,the compound has a maximum emission of about 630 nm to about 700 nm. Inembodiments, the compound has a maximum emission of about 640 nm toabout 680 nm. In embodiments, the compound has a maximum emission ofabout 650 nm to about 680 nm. In embodiments, the compound has a maximumemission of about 700 nm to about 800 nm.

In embodiments, the compound has a maximum emission of about 640 nm, 641nm, 642 nm, 643 nm, 644 nm, 645 nm, 646 nm, 647 nm, 648 nm, 649 nm, 650nm, 651 nm, 652 nm, 653 nm, 654 nm, 655 nm, 656 nm, 657 nm, 658 nm, 659nm, 660 nm, 661 nm, 662 nm, 663 nm, 664 nm, 665 nm, 666 nm, 667 nm, 668nm, 669 nm, 670 nm, 671 nm, 672 nm, 673 nm, 674 nm, 675 nm, 676 nm, 677nm, 678 nm, 679 nm, or about 680 nm. In embodiments, the compound has amaximum emission of about 680 nm, 681 nm, 682 nm, 683 nm, 684 nm, 685nm, 686 nm, 687 nm, 688 nm, 689 nm, 690 nm, 691 nm, 692 nm, 693 nm, 694nm, 695 nm, 696 nm, 697 nm, 698 nm, 699 nm, 700 nm, 701 nm, 702 nm, 703nm, 704 nm, 705 nm, 706 nm, 707 nm, 708 nm, 709 nm, 710 nm, 711 nm, 712nm, 713 nm, 714 nm, 715 nm, 716 nm, 717 nm, 718 nm, 719 nm, 720 nm, 721nm, 722 nm, 723 nm, 724 nm, 725 nm, 726 nm, 727 nm, 728 nm, 729 nm, 730nm, 731 nm, 732 nm, 733 nm, 734 nm, 735 nm, 736 nm, 737 nm, 738 nm, 739nm, 740 nm, 741 nm, 742 nm, 743 nm, 744 nm, 745 nm, 746 nm, 747 nm, 748nm, 749 nm, 750 nm, 751 nm, 752 nm, 753 nm, 754 nm, 755 nm, 756 nm, 757nm, 758 nm, 759 nm, 760 nm, 761 nm, 762 nm, 763 nm, 764 nm, 765 nm, 766nm, 767 nm, 768 nm, 769 nm, 770 nm, 771 nm, 772 nm, 773 nm, 774 nm, 775nm, 776 nm, 777 nm, 778 nm, 779 nm, 780 nm, 781 nm, 782 nm, 783 nm, 784nm, 785 nm, 786 nm, 787 nm, 788 nm, 789 nm, 790 nm, 791 nm, 792 nm, 793nm, 794 nm, 795 nm, 796 nm, 797 nm, 798 nm, 799 nm, or 800 nm.

In an aspect is provided a nucleotide covalently bound to a monovalentcompound described herein (e.g., wherein the R⁸ moiety of a compounddescribed herein has reacted with a bioconjugate reactive group to forma bioconjugate linker thereby covalently bonding the monovalent compoundto the monovalent nucleotide).

In an aspect is provided a nucleoside covalently bound to a monovalentcompound described herein (e.g., wherein the R⁸ moiety of a compounddescribed herein has reacted with a bioconjugate reactive group to forma bioconjugate linker thereby covalently bonding the monovalent compoundto the monovalent nucleoside).

In embodiments, the monovalent compound is a compound described herein,wherein the R⁸ moiety has reacted with a bioconjugate reactive group,wherein the monovalent compound has the formula:

wherein R², R³, R⁴, R⁵, R⁶, R⁷, L¹, L², L³, R¹¹, R¹², R⁹, and R¹⁰ are asdescribed herein, including embodiments.

In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, L¹, L², R¹¹, R¹², R⁹, and R¹⁰ are asdescribed herein, including embodiments. The symbol B is a base oranalogue thereof. The symbol

in the formula above refers to an attachment point to a phosphate (e.g.,monophosphate or polyphosphate), a hydrogen, or a reversible terminatormoiety (e.g., a substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl moiety).

In embodiments, the compound has the formula:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, L¹, L², R¹¹, R¹², R⁹, and R¹⁰ are asdescribed herein, including embodiments. The symbol B is a base oranalogue thereof. The symbol

in the formula above refers to an attachment point to a phosphate (e.g.,monophosphate or polyphosphate), a hydrogen, or a reversible terminatormoiety (e.g., a substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl moiety).

In embodiments, the compound has the formula:

wherein R², R³, R⁴, R⁵, R⁶, R⁷, L¹, L², R¹¹, R¹², R⁹, and R¹⁰ are asdescribed herein, including embodiments. The symbol B is a base oranalogue thereof. The symbol

in the formula above refers to an attachment point to a phosphate (e.g.,monophosphate or polyphosphate), a hydrogen, or a reversible terminatormoiety (e.g., a substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl moiety).

In embodiments, the compound has the formula:

wherein R², R³, R⁴, R⁵, R⁶, R⁷, L¹, L², R¹¹, R¹², R⁹, and R¹⁰ are asdescribed herein, including embodiments. The symbol B is a base oranalogue thereof. The symbol

in the formula above refers to an attachment point to a phosphate (e.g.,monophosphate or polyphosphate), a hydrogen, or a reversible terminatormoiety (e.g., a substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl moiety).

In embodiments, the compound has the formula:

wherein R², R³, R⁴, R⁵, R⁶, R⁷, L¹, L², R¹¹, R¹², R⁹, and R¹⁰ are asdescribed herein, including embodiments. The symbol

in the formula above refers to an attachment point to a phosphate (e.g.,monophosphate or polyphosphate), a hydrogen, or a reversible terminatormoiety (e.g., a substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl moiety). L³ is independently

and R¹ is as described herein, including in embodiments. The symbol B isa base or analogue thereof.

In embodiments, the compound has the formula:

wherein R², R³, R⁶, R⁷, L¹, L², R¹¹, R¹², R⁹, and R¹⁰ are as describedherein, including embodiments. The symbol

in the formula above refers to an attachment point to a phosphate (e.g.,monophosphate or polyphosphate), a hydrogen, or a reversible terminatormoiety (e.g., a substituted or unsubstituted alkyl, or substituted orunsubstituted heteroalkyl moiety). L³ is independently

and R¹ is as described herein, including in embodiments. The symbol B isa base or analogue thereof.

In embodiments, the compound has the formula:

wherein R², R³, R²⁴, R⁵, R⁶, R²⁵, L¹, L², R¹¹, z23, z24, and R¹² are asdescribed herein, including embodiments. The symbol

in the formula above refers to an attachment point to a phosphate (e.g.,monophosphate or polyphosphate), a hydrogen, or a reversible terminatormoiety (e.g., a substituted or unsubstituted alkyl or substituted orunsubstituted heteroalkyl moiety). L³ is independently

and R¹ is as described herein, including in embodiments. The symbol B isa base or analogue thereof.

In embodiments, B is cytosine or a derivative thereof, guanine or aderivative thereof, adenine or a derivative thereof, thymine or aderivative thereof, uracil or a derivative thereof, hypoxanthine or aderivative thereof, xanthine or a derivative thereof, deaza-adenine or aderivative thereof, deaza-guanine or a derivative thereof,deaza-hypoxanthine or a derivative thereof, 7-methylguanine or aderivative thereof, 5,6-dihydrouracil or a derivative thereof,5-methylcytosine or a derivative thereof, or 5-hydroxymethylcytosine ora derivative thereof.

In embodiments, B is a divalent cytosine or a derivative thereof,divalent guanine or a derivative thereof, divalent adenine or aderivative thereof, divalent thymine or a derivative thereof, divalenturacil or a derivative thereof, divalent hypoxanthine or a derivativethereof, divalent xanthine or a derivative thereof, divalent7-methylguanine or a derivative thereof, divalent 5,6-dihydrouracil or aderivative thereof, divalent 5-methylcytosine or a derivative thereof,or divalent 5-hydroxymethylcytosine or a derivative thereof.

In embodiments, B is

In embodiments, B is

In embodiments, B is

In embodiments, B is

In embodiments, B is

Altering the pH and/or temperature could have a dramatic effect on thefluorescence intensity of some fluorophores. For example, it is widelyknown that the fluorescent intensity of fluorescein is highlysusceptible to changes in pH. In embodiments, the spectral properties(e.g., the emission wavelength and/or the emission intensity) of thecompounds described herein do not significantly increase or decrease asa result of a change in the pH. In embodiments, the spectral properties(e.g., the emission wavelength and/or the emission intensity) of thecompounds described herein do not significantly decrease as a result ofa change in the pH. In embodiments, the emission intensity (i.e., theresulting fluorescence of the compound described herein followingexcitation) of the compounds described herein does not decrease as aresult of a change in the pH. In embodiments, the emission intensity(i.e., the resulting fluorescence of the compound described hereinfollowing excitation) of the compounds described herein does notdecrease more than 10%, 20%, or 30% as a result of a change in the pH.In embodiments, the fluorescence intensity of the compounds describedherein is maintained over a pH range of about 4.0 to about 11.0. Inembodiments, the fluorescence intensity of the compounds describedherein is maintained over a pH range of about 8.0 to about 11.0. Inembodiments, the fluorescence intensity of the compounds describedherein is maintained over a pH range of about 9.0 to about 11.0.

In embodiments, the spectral properties (e.g., the emission wavelengthand/or the emission intensity) of the compounds described herein do notsignificantly increase or decrease as a result of a change in thetemperature. In embodiments, the spectral properties (e.g., the emissionwavelength and/or the emission intensity) of the compounds describedherein do not significantly decrease as a result of a change in thetemperature. In embodiments, the emission intensity (i.e., the resultingfluorescence of the compound described herein following excitation) ofthe compounds described herein does not decrease as a result of a changein the temperature. In embodiments, the emission intensity (i.e., theresulting fluorescence of the compound described herein followingexcitation) of the compounds described herein does not decrease morethan 10%, 20%, or 30% as a result of a change in the temperature. Inembodiments, the fluorescence intensity of the compounds describedherein is maintained at a temperature of about 55° C., 56° C., 57° C.,58° C., 59° C., 60° C., 61° C., 62° C., 63° C., 64° C., 65° C., 66° C.,67° C., 68° C., 69° C., 70° C., 71° C., 72° C., 73° C., 74° C., 75° C.,76° C., 77° C., 78° C., 79° C., or 80° C.

In embodiments, when R¹ is substituted, R¹ is substituted with one ormore first substituent denoted by R^(1.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(1.1) substituent group issubstituted, the R^(1.1) substituent group is substituted with one ormore second substituent groups denoted by R^(1.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(1.2) substituent group issubstituted, the R^(1.2) substituent group is substituted with one ormore third substituent groups denoted by R^(1.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R¹, R^(1.1), R^(1.2), and R^(1.3)have values corresponding to the values of R^(WW), R^(WW.1), R^(WW.2),and R^(WW.3), respectively, as explained in the definitions sectionabove in the description of “first substituent group(s)”, whereinR^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R¹, R^(1.1),R^(1.2), and R^(1.3), respectively.

In embodiments, when R^(1A) is substituted, R^(1A) is substituted withone or more first substituent groups denoted by R^(1A.1) as explained inthe definitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(1A.1) substituent group issubstituted, the R^(1A.1) substituent group is substituted with one ormore second substituent groups denoted by R^(1A.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(1A.2) substituent group issubstituted, the R^(1A.2) substituent group is substituted with one ormore third substituent groups denoted by R^(1A.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R^(1A), R^(1A.1), R^(1A.2), andR^(1A.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R^(1A),R^(1A.1), R^(1A.2), and R^(1A.3), respectively.

In embodiments, when R² is substituted, R² is substituted with one ormore first substituent groups denoted by R^(2.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(2.1) substituent group issubstituted, the R^(2.1) substituent group is substituted with one ormore second substituent groups denoted by R^(2.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(2.2) substituent group issubstituted, the R^(2.2) substituent group is substituted with one ormore third substituent groups denoted by R^(2.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R², R^(2.1), R^(2.2), and R^(2.3)have values corresponding to the values of R^(WW), R^(WW.1), R^(WW.2),and R^(WW.3), respectively, as explained in the definitions sectionabove in the description of “first substituent group(s)”, whereinR^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R², R^(2.1),R^(2.2), and R^(2.3), respectively.

In embodiments, when R³ is substituted, R³ is substituted with one ormore first substituent groups denoted by R^(3.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(3.1) substituent group issubstituted, the R^(3.1) substituent group is substituted with one ormore second substituent groups denoted by R^(3.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(3.2) substituent group issubstituted, the R^(3.2) substituent group is substituted with one ormore third substituent groups denoted by R^(3.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R³, R^(3.1), R^(3.2), and R^(3.3)have values corresponding to the values of R^(WW), R^(WW.1), R^(WW.2),and R^(WW.3), respectively, as explained in the definitions sectionabove in the description of “first substituent group(s)”, whereinR^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R³, R^(3.1),R^(3.2) and R^(3.3), respectively.

In embodiments, when R⁴ is substituted, R⁴ is substituted with one ormore first substituent groups denoted by R^(4.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(4.1) substituent group issubstituted, the R^(4.1) substituent group is substituted with one ormore second substituent groups denoted by R^(4.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(4.2) substituent group issubstituted, the R^(4.2) substituent group is substituted with one ormore third substituent groups denoted by R^(4.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R⁴, R^(4.1), R^(4.2), and R^(4.3)have values corresponding to the values of R^(WW), R^(WW.1), R^(WW.2),and R^(WW.3), respectively, as explained in the definitions sectionabove in the description of “first substituent group(s)”, whereinR^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R⁴, R^(4.1),R^(4.2) and R^(4.3), respectively.

In embodiments, when R⁵ is substituted, R⁵ is substituted with one ormore first substituent groups denoted by R^(5.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(5.1) substituent group issubstituted, the R^(5.1) substituent group is substituted with one ormore second substituent groups denoted by R^(5.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(5.2) substituent group issubstituted, the R^(5.2) substituent group is substituted with one ormore third substituent groups denoted by R^(5.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R⁵, R^(5.1), R^(5.2), and R^(5.3)have values corresponding to the values of R^(WW), R^(WW.1), R^(WW.2),and R^(WW.3), respectively, as explained in the definitions sectionabove in the description of “first substituent group(s)”, whereinR^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R⁵, R^(5.1),R^(5.2) and R^(5.3), respectively.

In embodiments, when R⁶ is substituted, R⁶ is substituted with one ormore first substituent groups denoted by R^(6.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(6.1) substituent group issubstituted, the R^(6.1) substituent group is substituted with one ormore second substituent groups denoted by R⁶ as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(6.2) substituent group issubstituted, the R^(6.2) substituent group is substituted with one ormore third substituent groups denoted by R^(6.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R⁶, R^(6.1), R^(6.2), and R^(6.3)have values corresponding to the values of R^(WW), R^(WW.1), R^(WW.2),and R^(WW.3), respectively, as explained in the definitions sectionabove in the description of “first substituent group(s)”, whereinR^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R⁶, R^(6.1),R^(6.2) and R^(6.3), respectively.

In embodiments, when R⁷ is substituted, R⁷ is substituted with one ormore first substituent groups denoted by R^(7.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(7.1) substituent group issubstituted, the R^(7.1) substituent group is substituted with one ormore second substituent groups denoted by R^(7.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(7.2) substituent group issubstituted, the R^(7.2) substituent group is substituted with one ormore third substituent groups denoted by R^(7.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R⁷, R^(7.1), R^(7.2), and R^(7.3)have values corresponding to the values of R^(WW), R^(WW.1), R^(WW.2),and R^(WW.3), respectively, as explained in the definitions sectionabove in the description of “first substituent group(s)”, whereinR^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R⁷, R^(7.1),R^(7.2), and R^(7.3), respectively.

In embodiments, when R⁸ is substituted, R⁸ is substituted with one ormore first substituent groups denoted by R^(8.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(8.1) substituent group issubstituted, the R^(8.1) substituent group is substituted with one ormore second substituent groups denoted by R^(8.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(8.2) substituent group issubstituted, the R^(8.2) substituent group is substituted with one ormore third substituent groups denoted by R^(8.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R⁸, R^(8.1), R^(8.2), and R^(8.3)have values corresponding to the values of R^(WW), R^(WW.1), R^(WW.2),and R^(WW.3), respectively, as explained in the definitions sectionabove in the description of “first substituent group(s)”, whereinR^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R⁸, R^(8.1),R^(8.2) and R^(8.3), respectively.

In embodiments, when R⁹ is substituted, R⁹ is substituted with one ormore first substituent groups denoted by R^(9.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(9.1) substituent group issubstituted, the R^(9.1) substituent group is substituted with one ormore second substituent groups denoted by R^(9.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(9.2) substituent group issubstituted, the R^(9.2) substituent group is substituted with one ormore third substituent groups denoted by R^(9.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R⁹, R^(9.1), R^(9.2), and R^(9.3)have values corresponding to the values of R^(WW), R^(WW.1), R^(WW.2),and R^(WW.3), respectively, as explained in the definitions sectionabove in the description of “first substituent group(s)”, whereinR^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R⁹, R^(9.1),R^(9.2), and R^(9.3), respectively.

In embodiments, when R¹⁰ is substituted, R¹⁰ is substituted with one ormore first substituent groups denoted by R^(10.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(10.1) substituent group issubstituted, the R^(10.1) substituent group is substituted with one ormore second substituent groups denoted by R^(10.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(10.2) substituent group issubstituted, the R^(10.2) substituent group is substituted with one ormore third substituent groups denoted by R^(10.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R¹⁰, R^(10.1), R^(10.2), andR^(10.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R¹⁰,R^(10.1), R^(10.2), and R^(10.3), respectively.

In embodiments, when R¹¹ is substituted, R¹¹ is substituted with one ormore first substituent groups denoted by R^(11.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(11.1) substituent group issubstituted, the R^(11.1) substituent group is substituted with one ormore second substituent groups denoted by R^(11.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(11.2) substituent group issubstituted, the R^(11.2) substituent group is substituted with one ormore third substituent groups denoted by R^(11.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R¹¹, R^(11.1), R^(11.2), andR^(11.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R¹¹,R^(11.1), R^(11.2), and R^(11.3), respectively.

In embodiments, when R¹² is substituted, R¹² is substituted with one ormore first substituent groups denoted by R^(12.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(12.1) substituent group issubstituted, the R^(12.1) substituent group is substituted with one ormore second substituent groups denoted by R^(12.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(12.2) substituent group issubstituted, the R^(12.2) substituent group is substituted with one ormore third substituent groups denoted by R^(12.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R¹², R^(12.1), R^(12.2), andR^(12.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R¹²,R^(12.1), R^(12.2), and R^(12.3), respectively.

In embodiments, when R¹⁴ is substituted, R¹⁴ is substituted with one ormore first substituent groups denoted by R^(14.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(14.1) substituent group issubstituted, the R^(14.1) substituent group is substituted with one ormore second substituent groups denoted by R^(14.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(14.2) substituent group issubstituted, the R^(14.2) substituent group is substituted with one ormore third substituent groups denoted by R^(14.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R¹⁴, R^(14.1), R^(14.2), andR^(14.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R¹⁴,R^(14.1), R^(14.2), and R^(14.3), respectively.

In embodiments, when R¹⁵ is substituted, R¹⁵ is substituted with one ormore first substituent groups denoted by R^(15.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(15.1) substituent group issubstituted, the R^(15.1) substituent group is substituted with one ormore second substituent groups denoted by R^(15.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(15.2) substituent group issubstituted, the R^(15.2) substituent group is substituted with one ormore third substituent groups denoted by R^(15.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R¹⁵, R^(15.1), R^(15.2), andR^(15.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R¹⁵,R^(15.1), R^(15.2) and R^(15.3), respectively.

In embodiments, when R¹⁶ is substituted, R¹⁶ is substituted with one ormore first substituent groups denoted by R^(16.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(16.1) substituent group issubstituted, the R^(16.1) substituent group is substituted with one ormore second substituent groups denoted by R^(16.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(16.2) substituent group issubstituted, the R^(16.2) substituent group is substituted with one ormore third substituent groups denoted by R^(16.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R¹⁶, R^(16.1), R^(16.2), andR^(16.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R¹⁶,R^(16.1), R^(16.2), and R^(16.3), respectively.

In embodiments, when R¹⁷ is substituted, R¹⁷ is substituted with one ormore first substituent groups denoted by R^(17.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(17.1) substituent group issubstituted, the R^(17.1) substituent group is substituted with one ormore second substituent groups denoted by R^(17.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(17.2) substituent group issubstituted, the R^(17.2) substituent group is substituted with one ormore third substituent groups denoted by R^(17.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R¹⁷, R^(17.1), R^(17.2), andR^(17.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R¹⁷,R^(17.1), R^(17.2), and R^(17.3), respectively.

In embodiments, when R¹⁸ is substituted, R¹⁸ is substituted with one ormore first substituent groups denoted by R^(18.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(18.1) substituent group issubstituted, the R^(18.1) substituent group is substituted with one ormore second substituent groups denoted by R^(18.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(18.2) substituent group issubstituted, the R^(18.2) substituent group is substituted with one ormore third substituent groups denoted by R^(18.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R¹⁸, R^(18.1), R^(18.2), andR^(18.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R¹⁸,R^(18.1), R^(18.2), and R^(18.3), respectively.

In embodiments, when R¹⁹ is substituted, R¹⁹ is substituted with one ormore first substituent groups denoted by R^(19.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(19.1) substituent group issubstituted, the R^(19.1) substituent group is substituted with one ormore second substituent groups denoted by R^(19.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(19.2) substituent group issubstituted, the R^(19.2) substituent group is substituted with one ormore third substituent groups denoted by R^(19.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R¹⁹, R^(19.1), R^(19.2), andR^(19.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R¹⁹,R^(19.1), R^(19.2), and R^(19.3), respectively.

In embodiments, when R²⁰ is substituted, R²⁰ is substituted with one ormore first substituent groups denoted by R^(20.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(20.1) substituent group issubstituted, the R^(20.1) substituent group is substituted with one ormore second substituent groups denoted by R^(20.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(20.2) substituent group issubstituted, the R^(20.2) substituent group is substituted with one ormore third substituent groups denoted by R^(20.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R²⁰, R^(20.1), R^(20.2), andR^(20.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R²⁰,R^(20.1), R^(20.2), and R^(20.3), respectively.

In embodiments, when R²³ is substituted, R²³ is substituted with one ormore first substituent groups denoted by R^(23.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(23.1) substituent group issubstituted, the R^(23.1) substituent group is substituted with one ormore second substituent groups denoted by R^(23.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(23.2) substituent group issubstituted, the R^(23.2) substituent group is substituted with one ormore third substituent groups denoted by R^(23.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R²³, R^(23.1), R^(23.2), andR^(23.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R²³,R^(23.1), R^(23.2), and R^(23.3), respectively.

In embodiments, when R²⁴ is substituted, R²⁴ is substituted with one ormore first substituent groups denoted by R^(24.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(24.1) substituent group issubstituted, the R^(24.1) substituent group is substituted with one ormore second substituent groups denoted by R^(24.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(24.2) substituent group issubstituted, the R^(24.2) substituent group is substituted with one ormore third substituent groups denoted by R^(24.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R²⁴, R^(24.1), R^(24.2), andR^(24.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R²⁴,R^(24.1), R^(24.2), and R^(24.3), respectively.

In embodiments, when R²⁵ is substituted, R²⁵ is substituted with one ormore first substituent groups denoted by R^(25.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(25.1) substituent group issubstituted, the R^(25.1) substituent group is substituted with one ormore second substituent groups denoted by R^(25.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(25.2) substituent group issubstituted, the R^(25.2) substituent group is substituted with one ormore third substituent groups denoted by R^(25.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R²⁵, R^(25.1), R^(25.2), andR^(25.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R²⁵,R^(25.1), R^(25.2), and R^(25.3), respectively.

In embodiments, when R²⁶ is substituted, R²⁶ is substituted with one ormore first substituent groups denoted by R^(26.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(26.1) substituent group issubstituted, the R^(26.1) substituent group is substituted with one ormore second substituent groups denoted by R^(26.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(26.2) substituent group issubstituted, the R^(26.2) substituent group is substituted with one ormore third substituent groups denoted by R^(26.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R²⁶, R^(26.1), R^(26.2), andR^(26.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R²⁶,R^(26.1), R^(26.2), and R^(26.3), respectively.

In embodiments, when R⁵⁴ is substituted, R⁵⁴ is substituted with one ormore first substituent groups denoted by R^(54.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(54.1) substituent group issubstituted, the R^(54.1) substituent group is substituted with one ormore second substituent groups denoted by R^(54.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(54.2) substituent group issubstituted, the R^(54.2) substituent group is substituted with one ormore third substituent groups denoted by R^(54.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, R⁵⁴, R^(54.1), R^(54.2), andR^(54.3) have values corresponding to the values of R^(WW), R^(WW.1),R^(WW.2), and R^(WW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspond to R⁵⁴,R^(54.1), R^(54.2), and R^(54.3), respectively.

In embodiments, when R^(54A) is substituted, R^(54A) is substituted withone or more first substituent groups denoted by R^(54A.1) as explainedin the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(54A.1) substituentgroup is substituted, the R^(54A.1) substituent group is substitutedwith one or more second substituent groups denoted by R^(54A.2) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(54A.2) substituentgroup is substituted, the R^(54A.2) substituent group is substitutedwith one or more third substituent groups denoted by R^(54A.3) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In the above embodiments, R^(54A), R^(54A.1),R^(54A.2), and R^(54A.3) have values corresponding to the values ofR^(WW), R^(WW.1), R^(WW.2), and R^(WW.3), respectively, as explained inthe definitions section above in the description of “first substituentgroup(s)”, wherein R^(WW), R^(WW.1), R^(WW.2), and R^(WW.3) correspondto R^(54A), R^(54A.1), R^(54A.2), and R^(54A.3), respectively.

In embodiments, when L¹ is substituted, L¹ is substituted with one ormore first substituent groups denoted by R^(L1.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(L1.1) substituent group issubstituted, the R^(L1.1) substituent group is substituted with one ormore second substituent groups denoted by R^(L1.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(L1.2) substituent group issubstituted, the R^(L1.2) substituent group is substituted with one ormore third substituent groups denoted by R^(L1.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, L¹, R^(L1.1), R^(L1.2), andR^(L1.3) have values corresponding to the values of L^(WW), R^(LWW.1),R^(LWW.2), and R^(LWW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein L^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3) are L, R^(LWW.1),R^(LWW.2), and R^(LWW.3), respectively.

In embodiments, when L^(1A) is substituted, L^(1A) is substituted withone or more first substituent groups denoted by R^(L1A.1) as explainedin the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L1A.1) substituentgroup is substituted, the R^(L1A.1) substituent group is substitutedwith one or more second substituent groups denoted by R^(L1A.2) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L1A.2) substituentgroup is substituted, the R^(L1A.2) substituent group is substitutedwith one or more third substituent groups denoted by R^(L1A.3) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In the above embodiments, L^(1A), R^(L1A.1),R^(L1A.2), and R^(L1A.3) have values corresponding to the values ofL^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3), respectively, as explainedin the definitions section above in the description of “firstsubstituent group(s)”, wherein L^(WW), R^(LWW.1), R^(LWW.2), andR^(LWW.3) are L^(1A), R^(L1A.1), R^(L1A.2), and R^(L1A.3), respectively.

In embodiments, when L^(1B) is substituted, L^(1B) is substituted withone or more first substituent groups denoted by R^(L1B.1) as explainedin the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L1B.1) substituentgroup is substituted, the R^(L1B.1) substituent group is substitutedwith one or more second substituent groups denoted by R^(L1B.2) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L1B.2) substituentgroup is substituted, the R^(L1B.2) substituent group is substitutedwith one or more third substituent groups denoted by R^(L1B.3) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In the above embodiments, L^(1B), R^(L1B.1),R^(L1B.2), and R^(L1B.3) have values corresponding to the values ofL^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3), respectively, as explainedin the definitions section above in the description of “firstsubstituent group(s)”, wherein L^(WW), R^(LWW.1), R^(LWW.2), andR^(LWW.3) are L^(1B), R^(L1B.1), R^(L1B.2), and R^(L1B.3), respectively.

In embodiments, when L^(1C) is substituted, L^(1C) is substituted withone or more first substituent groups denoted by R^(L1C.1) as explainedin the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L1C.1) substituentgroup is substituted, the R^(L1C.1) substituent group is substitutedwith one or more second substituent groups denoted by R^(L1C.2) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L1C.2) substituentgroup is substituted, the R^(L1C.2) substituent group is substitutedwith one or more third substituent groups denoted by R^(L1C.3) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In the above embodiments, L^(1C), R^(L1C.1),R^(L1C.2), and R^(L1C.3) have values corresponding to the values ofL^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3), respectively, as explainedin the definitions section above in the description of “firstsubstituent group(s)”, wherein L^(WW), R^(LWW.1), R^(LWW.2), andR^(LWW.3) are L^(1C), R^(L1C.1), R^(L1C.2), and R^(L1C.3), respectively.

In embodiments, when L^(1D) is substituted, L^(1D) is substituted withone or more first substituent groups denoted by R^(L1D.1) as explainedin the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L1D.1) substituentgroup is substituted, the R^(L1D.1) substituent group is substitutedwith one or more second substituent groups denoted by R^(L1D.2) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L1D.2) substituentgroup is substituted, the R^(L1D.2) substituent group is substitutedwith one or more third substituent groups denoted by R^(L1D.3) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In the above embodiments, L^(1D), R^(L1D.1),R^(L1D.2), and R^(L1D.3) have values corresponding to the values ofL^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3), respectively, as explainedin the definitions section above in the description of “firstsubstituent group(s)”, wherein L^(WW), R^(LWW.1), R^(LWW.2), andR^(LWW.3) are L^(1D), R^(L1D.1), R^(L1D.2), and R^(L1D.3), respectively.

In embodiments, when L^(1E) is substituted, L^(1E) is substituted withone or more first substituent groups denoted by R^(L1E.1) as explainedin the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L1E.1) substituentgroup is substituted, the R^(L1E.1) substituent group is substitutedwith one or more second substituent groups denoted by R^(L1E.2) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L1E.2) substituentgroup is substituted, the R^(L1E.2) substituent group is substitutedwith one or more third substituent groups denoted by R^(L1E.3) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In the above embodiments, L^(1E), R^(L1E.1),R^(L1E.2), and R^(L1E.3) have values corresponding to the values ofL^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3), respectively, as explainedin the definitions section above in the description of “firstsubstituent group(s)”, wherein L^(WW), R^(LWW.1), R^(LWW.2), andR^(LWW.3) are L^(1E), R^(L1E.1), R^(L1E.2), and R^(L1E.3), respectively.

In embodiments, when L² is substituted, L² is substituted with one ormore first substituent groups denoted by R^(L2.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(L2.1) substituent group issubstituted, the R^(L2.1) substituent group is substituted with one ormore second substituent groups denoted by R^(L2.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(L2.2) substituent group issubstituted, the R^(L2.2) substituent group is substituted with one ormore third substituent groups denoted by R^(L2.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, L², R^(L2.1), R^(L2.2), andR^(L2.3) have values corresponding to the values of L^(WW), R^(LWW.1),R^(LWW.2), and R^(LWW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein L^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3) are L², R^(L2.1),R^(L2.2), and R^(L2.3), respectively.

In embodiments, when L^(2A) is substituted, L^(2A) is substituted withone or more first substituent groups denoted by R^(L2A.1) as explainedin the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L2A.1) substituentgroup is substituted, the R^(L2A.1) substituent group is substitutedwith one or more second substituent groups denoted by R^(L2A.2) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L2A.2) substituentgroup is substituted, the R^(L2A.2) substituent group is substitutedwith one or more third substituent groups denoted by R^(L2A.3) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In the above embodiments, L^(2A), R^(L2A.1),R^(L2A.2), and R^(L2A.3) have values corresponding to the values ofL^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3), respectively, as explainedin the definitions section above in the description of “firstsubstituent group(s)”, wherein L^(WW), R^(LWW.1), R^(LWW.2), andR^(LWW.3) are L^(2A), R^(L2A.1), R^(L2A.2), and R^(L2A.3), respectively.

In embodiments, when L^(2B) is substituted, L^(2B) is substituted withone or more first substituent groups denoted by R^(L2B.1) as explainedin the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L2B.1) substituentgroup is substituted, the R^(L2B.1) substituent group is substitutedwith one or more second substituent groups denoted by R^(L2B.2) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L2B.2) substituentgroup is substituted, the R^(L2B.2) substituent group is substitutedwith one or more third substituent groups denoted by R^(L2B.3) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In the above embodiments, L^(2B), R^(L2B.1),R^(L2B.2), and R^(L2B.3) have values corresponding to the values ofL^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3), respectively, as explainedin the definitions section above in the description of “firstsubstituent group(s)”, wherein L^(WW), R^(LWW.1), R^(LWW.2), andR^(LWW.3) are L^(2B), R^(L2B.1), R^(L2B.2), and R^(L2B.3), respectively.

In embodiments, when L^(2C) is substituted, L^(2C) is substituted withone or more first substituent groups denoted by R^(L2C.1) as explainedin the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L2C.1) substituentgroup is substituted, the R^(L2C.1) substituent group is substitutedwith one or more second substituent groups denoted by R^(L2C.2) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L2C.2) substituentgroup is substituted, the R^(L2C.2) substituent group is substitutedwith one or more third substituent groups denoted by R^(L2C.3) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In the above embodiments, L^(2C), R^(L2C.1),R^(L2C.2), and R^(L2C.3) have values corresponding to the values ofL^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3), respectively, as explainedin the definitions section above in the description of “firstsubstituent group(s)”, wherein L^(WW), R^(LWW.1), R^(LWW.2), andR^(LWW.3) are L^(2C), R^(L2C.1), R^(L2C.2), and R^(L2C.3), respectively.

In embodiments, when L^(2D) is substituted, L^(2D) is substituted withone or more first substituent groups denoted by R^(L2D.1) as explainedin the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L2D.1) substituentgroup is substituted, the R^(L2D.1) substituent group is substitutedwith one or more second substituent groups denoted by R^(L2D.2) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L2D.2) substituentgroup is substituted, the R^(L2D.2) substituent group is substitutedwith one or more third substituent groups denoted by R^(L2D.3) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In the above embodiments, L^(2D), R^(L2D.1),R^(L2D.2), and R^(L2D.3) have values corresponding to the values ofL^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3), respectively, as explainedin the definitions section above in the description of “firstsubstituent group(s)”, wherein L^(WW), R^(LWW.1), R^(LWW.2), andR^(LWW.3) are L^(2D), R^(L2D.1), R^(L2D.2), and R^(L2D.3), respectively.

In embodiments, when L^(2E) is substituted, L^(2E) is substituted withone or more first substituent groups denoted by R^(L2E.1) as explainedin the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L2E.1) substituentgroup is substituted, the R^(L2E.1) substituent group is substitutedwith one or more second substituent groups denoted by R^(L2E.2) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In embodiments, when an R^(L2E.2) substituentgroup is substituted, the R^(L2E.2) substituent group is substitutedwith one or more third substituent groups denoted by R^(L2E.3) asexplained in the definitions section above in the description of “firstsubstituent group(s)”. In the above embodiments, L^(2E), R^(L2E.1),R^(L2E.2), and R^(L2E.3) have values corresponding to the values ofL^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3), respectively, as explainedin the definitions section above in the description of “firstsubstituent group(s)”, wherein L^(WW), R^(LWW.1), R^(LWW.2), andR^(LWW.3) are L^(2E), R^(L2E.1), R^(L2E.2), and R^(L2E.3), respectively.

In embodiments, when L³ is substituted, L³ is substituted with one ormore first substituent groups denoted by R^(L3.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(L3.1) substituent group issubstituted, the R^(L3.1) substituent group is substituted with one ormore second substituent groups denoted by R^(L3.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(L3.2) substituent group issubstituted, the R^(L3.2) substituent group is substituted with one ormore third substituent groups denoted by R^(L3.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, L³, R^(L3.1), R^(L3.2), andR^(L3.3) have values corresponding to the values of L^(WW), R^(LWW.1),R^(LWW.2), and R^(LWW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein L^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3) are L³, R^(L3.1),R^(L3.2), and R^(L3.3), respectively.

In embodiments, when L⁴ is substituted, L⁴ is substituted with one ormore first substituent groups denoted by R^(L4.1) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(L4.1) substituent group issubstituted, the R^(L4.1) substituent group is substituted with one ormore second substituent groups denoted by R^(L4.2) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In embodiments, when an R^(L4.2) substituent group issubstituted, the R^(L4.2) substituent group is substituted with one ormore third substituent groups denoted by R^(L4.3) as explained in thedefinitions section above in the description of “first substituentgroup(s)”. In the above embodiments, L⁴, R^(L4.1), R^(L4.2), andR^(L4.3) have values corresponding to the values of L^(WW), R^(LWW.1),R^(LWW.2), and R^(LWW.3), respectively, as explained in the definitionssection above in the description of “first substituent group(s)”,wherein L^(WW), R^(LWW.1), R^(LWW.2), and R^(LWW.3) are L⁴, R^(L4.1),R^(L4.2), and R^(L4.3), respectively.

In embodiments, the compounds described herein are not cell-permeable.In embodiments, the compounds described herein do not include aspirolactone moiety. In embodiments, the compounds described herein arenot capable (e.g., under standard, equilibrium conditions) of forming aspirolactone moiety, for example:

In embodiments, the compound is less than 20% in a spirolactone form. Inembodiments, the compound is less than 15% in a spirolactone form. Inembodiments, the compound is less than 10% in a spirolactone form. Inembodiments, the compound is less than 5% in a spirolactone form. Inembodiments, the compound is less than 4% in a spirolactone form. Inembodiments, the compound is less than 3% in a spirolactone form. Inembodiments, the compound is less than 2% in a spirolactone form. Inembodiments, the compound is less than 1% in a spirolactone form.

In embodiments, the compounds described herein do not include aspirolactam moiety. In embodiments, the compounds described herein arenot capable (e.g., under standard, equilibrium conditions) of forming aspirolactam moiety, for example:

In embodiments, the compound is less than 20% in a spirolactam form. Inembodiments, the compound is less than 15% in a spirolactam form. Inembodiments, the compound is less than 10% in a spirolactam form. Inembodiments, the compound is less than 5% in a spirolactam form. Inembodiments, the compound is less than 4% in a spirolactam form. Inembodiments, the compound is less than 3% in a spirolactam form. Inembodiments, the compound is less than 2% in a spirolactam form. Inembodiments, the compound is less than 1% in a spirolactam form.

In embodiments, -L³-L¹-L²-R⁸ is not —CH₂—COOH. In embodiments,-L³-L¹-L²-R⁸ is not —CH₂—CO₂CH₃. In embodiments, -L³-L¹-L²-R⁸ is not—CH₃. In embodiments, -L³-L¹-L²-R⁸ is not —SO₃. In embodiments,-L³-L¹-L²-R⁸ is not hydrogen. In embodiments, -L³-L¹-L²-R⁸ is not —OH.In embodiments, -L³-L¹-L²-R⁸ is not —OCH₃. In embodiments, -L³-L¹-L²-R⁸is not —NO₂. In embodiments, -L³-L¹-L²-R⁸ is not —CH₂SO₃.

In embodiments, -L⁴-R¹⁴ is not —CH₂—COOH. In embodiments, -L⁴-R¹⁴ is not—CH₂—CO₂CH₃. In embodiments, -L⁴-R¹⁴ is not —CH₃. In embodiments,-L⁴-R¹⁴ is not —SO₃. In embodiments, -L⁴-R¹⁴ is not hydrogen. Inembodiments, -L⁴-R¹⁴ is not —OH. In embodiments, -L⁴-R¹⁴ is not —OCH₃.In embodiments, -L⁴-R¹⁴ is not —NO₂. In embodiments, -L⁴-R¹⁴ is not—CH₂SO₃.

In embodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atomdo not form a substituted or unsubstituted heterocycloalkyl. Inembodiments, R⁴ and R⁵ substituents bonded to the same nitrogen atom donot form a substituted heterocycloalkyl. In embodiments, R⁴ and R⁵substituents bonded to the same nitrogen atom do not form anunsubstituted heterocycloalkyl. In embodiments, R⁴ and R⁵ substituentsbonded to the same nitrogen atom do not form an unsubstituted 4 memberedheterocycloalkyl (e.g., azetidinyl). In embodiments, R⁶ and R⁷substituents bonded to the same nitrogen atom do not form a substitutedor unsubstituted heterocycloalkyl. In embodiments, R⁶ and R⁷substituents bonded to the same nitrogen atom do not form a substitutedheterocycloalkyl. In embodiments, R⁶ and R⁷ substituents bonded to thesame nitrogen atom do not form an unsubstituted heterocycloalkyl. Inembodiments, R⁶ and R⁷ substituents bonded to the same nitrogen atom donot form an unsubstituted 4 membered heterocycloalkyl (e.g.,azetidinyl).

In yet another aspect, is provided a kit including a compound describedherein. In embodiments, the kit further includes one or more sets ofinstructions. In embodiments, the kit includes nucleotides ornucleosides. Such kits will generally include at least one modifiednucleotide or nucleoside, wherein the modified nucleotide or nucleosideis covalently bound to a compound described herein. In embodiments, thekit may include a modified nucleotide, wherein the modified nucleotideis covalently bound to a compound described herein, and a secondmodified nucleotide, wherein the second modified nucleotide ornucleoside is covalently bound to a different fluorophore. Inembodiments, combinations of nucleotides may be provided as separateindividual components or as nucleotide mixtures. In embodiments, the kitmay further contain an unlabelled nucleotide. In embodiments, the kitincludes a compound described herein. In embodiments, the kit includes acompound described herein covalently bound to a nucleotide (e.g.,wherein the R⁸ moiety of a compound described herein has reacted with abioconjugate reactive group to form a bioconjugate linker therebycovalently bonding the compound described herein to the nucleotide). Inembodiments, the kit includes a compound described herein covalentlybound to a nucleoside (e.g., wherein the R⁸ moiety of a compounddescribed herein has reacted with a bioconjugate reactive group to forma bioconjugate linker thereby covalently bonding the compound describedherein to the nucleoside).

In embodiments, the kit includes a plurality (e.g., two, three, or four)of modified nucleotides, wherein each modified nucleotide is covalentlybound to a compound described herein. In embodiments, wherein the kitincludes a plurality of modified nucleotides, the different nucleotidesmay be labelled (e.g., covalently bonded) with different compounds(e.g., compounds described herein) that are spectrally distinguishablecompounds. As used herein, the term “spectrally distinguishablecompounds” refers to compounds as described herein that emit fluorescentenergy at wavelengths that can be distinguished by fluorescent detectionequipment when two or more such compounds are present in one sample. Inembodiments, when two modified nucleotides, each modified nucleotidecovalently bound to a compound described herein, are supplied within akit, the spectrally distinguishable compounds can be excited at the samewavelength, such as, for example by the same laser. In embodiments, whenfour modified nucleotides, each modified nucleotide covalently bound toa compound described herein, are supplied within a kit, two of thespectrally distinguishable compounds can both be excited at onewavelength and the other two spectrally distinguishable compounds canboth be excited at another wavelength.

In embodiments, the kit may include a DNA polymerase enzyme capable ofcatalyzing incorporation of the modified nucleotides into apolynucleotide. In embodiments, the kit includes a buffer. Inembodiments, the modified nucleotides may be provided in the kit in aconcentrated form to be diluted prior to use. In such embodiments, asuitable dilution buffer may also be included.

In an aspect is provided a nucleotide or oligonucleotide covalentlybound to a compound as described herein. In embodiments, when anucleotide or oligonucleotide covalently bound to a compound asdescribed herein, it may be referred to as a labelled nucleotide orlabelled oligonucleotide. The labelled nucleotide or oligonucleotide mayhave the label attached via a covalent linker. The labelled nucleotideor oligonucleotide may have the label attached to the C₅ position of apyrimidine base or the C₇ position of a 7-deaza purine base through alinker moiety. In embodiments, the labelled nucleotide oroligonucleotide may also have a 3′-O-polymerase compatible cleavablemoiety covalently attached to the ribose or deoxyribose sugar of thenucleotide.

In an aspect is provided an oligonucleotide including a compound asdescribed herein.

III. Methods of Use and Making

In an aspect is provided a method of detecting the presence of an agent,wherein the agent is covalently bound to a monovalent compound asdescribed herein (e.g., wherein R⁸ reacts to form part of the covalentlinker), wherein the agent is an oligonucleotide, protein, nucleotide,nucleoside, or compound. In embodiments, the agent is anoligonucleotide, protein, or compound. In embodiments, the agent is anoligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g., antibody orantibody fragment), or a compound. In embodiments, the method includes aspectroscopic measurement (e.g., measure the emission from the compounddescribed herein bonded to the agent). In embodiments, the spectroscopicmeasurement is an ultraviolet-visible spectroscopy measurement. Inembodiments, the compound is present in an effective amount. Inembodiments, the agent is a nucleic acid. In embodiments, the agent is anucleotide. In embodiments, the agent is a nucleoside. In embodiments,the method includes detecting in vitro. In embodiments, the methodincludes detecting in a nucleic acid sequencing device. In embodiments,the agent is a protein, a carbohydrate, a polysaccharide, aglycoprotein, a hormone, a receptor, an antigen, an antibody, or avirus.

In embodiments, the monovalent compound has the formula:

wherein L¹, L², L³, R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are asdescribed herein, including in embodiments.

In embodiments, the agent covalently bound to the monovalent compoundhas the formula:

wherein the symbol B is a divalent base or analogue thereof; and thesymbol

in formula (XI) or (XII) refers to an attachment point to hydrogen, aphosphate moiety, or a reversible terminator moiety. L¹, L², L³, R², R³,R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are as described herein, includingin embodiments.

In embodiments, the agent covalently bound to the monovalent compoundhas the formula:

wherein the symbol B is a divalent base or analogue thereof; and thesymbol

in formula (XIII) or (XIV) refers to an attachment point to hydrogen, aphosphate moiety, or a reversible terminator moiety. L¹, L², L³, R², R³,R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are as described herein, including inembodiments.

In embodiments, the method includes detecting the presence of anucleotide. In embodiments, the method includes detecting the presenceof a polynucleotide. Such polynucleotides may be DNA or RNA comprisedrespectively of deoxyribonucleotides or ribonucleotides joined inphosphodiester linkage. In embodiments, the polynucleotides includenaturally occurring nucleotides and/or non-naturally occurring (ormodified) nucleotides, that is modified nucleotides other than thelabelled nucleotides, or any combination thereof, provided that at leastone modified nucleotide is a nucleotide covalently bound to a compounddescribed herein. Polynucleotides according to the invention may alsoinclude non-natural backbone linkages and/or non-nucleotide chemicalmodifications.

In embodiments, the method includes (i) incorporating one or moremodified nucleotides into a polynucleotide, wherein the modifiednucleotide is a nucleotide covalently bound to a compound describedherein; and (ii) detecting the one or more modified nucleotide(s)incorporated into the polynucleotide by detecting or quantitativelymeasuring their fluorescence. In embodiments, the modified nucleotide isincorporated into a polynucleotide by a DNA polymerase (e.g., a DNApolymerase described herein). In embodiments, step (i) includesincubating a template polynucleotide strand with a reaction mixtureincluding modified nucleotides and a DNA polymerase under conditionsthat allow for the formation of a phosphodiester linkage between a free3′ hydroxyl group on a polynucleotide strand annealed to the templatepolynucleotide strand and a 5′ phosphate group on the modifiednucleotide. In embodiments, step (ii) may be carried out while thepolynucleotide strand is annealed to a template strand, or after adenaturation step in which the two strands are separated.

In embodiments, the method includes exposing the compound describedherein, which is bound to the agent, to electromagnetic radiation,wherein the electromagnetic radiation has a wavelength selected from 100to 1000 nm. In embodiments, the electromagnetic radiation has awavelength selected from about 500 nm to about 700 nm. In embodiments,the electromagnetic radiation has a wavelength selected from about 600nm to about 700 nm. In embodiments, the electromagnetic radiation has awavelength selected from about 620 nm to about 700 nm. In embodiments,the electromagnetic radiation has a wavelength selected from about 630nm to about 700 nm. In embodiments, the electromagnetic radiation has awavelength selected from about 630 nm to about 670 nm. In embodiments,the electromagnetic radiation has a wavelength selected from about 630nm to about 660 nm.

In embodiments, the method includes detecting the emission wavelength ofthe compound described herein bound to the agent (e.g., detecting theemission wavelength of the compound following exposure to theelectromagnetic radiation). In embodiments, the emission wavelength isabout 500 nm to about 700 nm. In embodiments, the emission wavelength isabout 500 nm to about 800 nm. In embodiments, the emission wavelength isabout 600 nm to about 700 nm. In embodiments, the emission wavelength isabout 620 nm to about 700 nm. In embodiments, the emission wavelength isabout 630 nm to about 700 nm. In embodiments, the emission wavelength isabout 640 nm to about 680 nm. In embodiments, the emission wavelength isabout 650 nm to about 680 nm. In embodiments, the emission wavelength isabout 650 nm to about 800 nm. In embodiments, the emission wavelength isabout 675 nm to about 800 nm. In embodiments, the emission wavelength isabout 700 nm to about 800 nm. In embodiments, the emission wavelength isabout 710 nm to about 800 nm. In embodiments, the emission wavelength isabout 720 nm to about 800 nm. In embodiments, the emission wavelength isabout 730 nm to about 800 nm. In embodiments, the emission wavelength isabout 740 nm to about 800 nm. In embodiments, the emission wavelength isabout 750 nm to about 800 nm. In embodiments, the emission wavelength isabout 760 nm to about 800 nm. In embodiments, the emission wavelength isabout 780 nm to about 800 nm. In embodiments, the emission wavelength isabout 790 nm to about 800 nm.

In another aspect is provided a method of making a compound, or saltthereof, having the formula:

the method including mixing compound A, compound B, and compound C in areaction vessel. L³, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹,and L² are as described herein, including in embodiments. Compound A hasthe formula:

R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are as described herein,including in embodiments. Compound B is a coupling reagent. Compound Chas the formula:

R¹, L¹, L², and R⁸ are as described herein, including embodiments. R¹³is a leaving group.

In another aspect is provided a method of making a compound, or saltthereof, having the formula:

the method including mixing compound A, compound B, and compound C in areaction vessel. R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², L¹,and L² are as described herein, including in embodiments. Compound A hasthe formula:

R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are as described herein,including in embodiments.

Compound B is a coupling reagent. Compound C has the formula:

R¹, L¹, L², and R⁸ are as described herein, including embodiments. R¹³is a leaving group (e.g., hydrogen).

In embodiments, Compound A has the formula:

R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are as described herein,including in embodiments. In embodiments, Compound A has the formula:

R², R³, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are as described herein, includingin embodiments. In embodiments, Compound A has the formula:

R², R³, R⁴, R⁵, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are as described herein,including in embodiments. In embodiments, Compound A has the formula:

R², R³, R⁶, R⁷, R⁹, R¹⁰, R¹¹, and R¹² are as described herein, includingin embodiments.

In embodiments, compound B is (PyBOP), (PyAOP), (PyClock), (HATU), or(HBTU).

In embodiments, compound B is

also referred to herein as PyBOP.

In embodiments, compound C is

wherein L¹ and L² are as described herein. In embodiments, compound C is

In embodiments, compound C is

In embodiments, compound C is

In embodiments, compound C is

In embodiments, compound C includes a cleavable moiety. In embodiments,compound C includes a cleavable linker. In embodiments, compound Cincludes a polymer.

In embodiments, the compound is a compound described herein, includingembodiments. In embodiments, the compound is a compound described herein(e.g., a compound described above in the section entitled “Compounds andkits”).

In embodiments, the compound is

In embodiments, the compound is

In embodiments, the method further includes adding a solvent to thereaction vessel. In embodiments, the method further includes adding anorganic solvent to the reaction vessel. In embodiments, the solvent istetrahydrofuran (THF), water, dimethylformamide (DMF), methanol,trimethylamine (TEA), or a combination thereof. In embodiments, thetemperature of the reaction is maintained below 0° C. In embodiments,the temperature of the reaction is maintained at −78° C. In embodiments,the method is a method described here (e.g., in a scheme).

In embodiments, the method further includes a reagent. In embodiments,the solvent or reagent isN,N,N′,N′-Tetramethyl-O—(N-succinimidyl)uronium tetrafluoroborate,O-[N-Succinimidyl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TSTU),N-Hydroxysuccinimide (NHS), dicyclohexylcarbodiimide (DCC),ethyl(dimethylaminopropyl) carbodiimide (EDC), N-Succinimidyl carbonate(DSC), N-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride(EDAC), N-Trifluoroacetoxy Succinimide (TFA-NHS), or1,1′-Carbonyldiimidazole (CDI). In embodiments, the solvent or reagentis benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBOP), 7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphoniumhexafluorophosphate (PyAOP),6-Chloro-benzotriazole-1-yloxy-tris-pyrrolidinophosphoniumhexafluorophosphate (PyClock),1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU), or2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU).

In another aspect is provided a method for detecting the presence of anucleotide, wherein the nucleotide is covalently bound to a compound(e.g., a compound described herein) (i.e., detect the presence of thecompound and thereby detect the presence of the covalently boundnucleotide).

In embodiments the method includes use of the modified nucleotides ornucleosides labelled with compounds described herein in a method ofnucleic acid sequencing, re-sequencing, whole genome sequencing, singlenucleotide polymorphism scoring, any other application involving thedetection of the modified nucleotide or nucleoside when incorporatedinto a polynucleotide, or any other application requiring the use ofpolynucleotides labelled with the modified nucleotides, wherein themodified nucleotide is a nucleotide covalently bound to a compounddescribed herein.

In an aspect is provided a method of nucleic acid sequencing includingincorporating a modified nucleotide (e.g., a nucleotide covalently boundto a compound described herein) into a polynucleotide.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

IV. Embodiments

Embodiment P1. A compound, or salt thereof, having the formula:

wherein,

-   -   R¹, R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, halogen,        —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F,        —CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂, —COOH, —CONH₂, —SH,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² and R³ are each independently substituted or unsubstituted        alkyl, or substituted or unsubstituted heteroalkyl;    -   R⁸ is hydrogen or a bioconjugate reactive moiety;    -   R⁹, R¹⁰, R¹¹, and R¹² are each independently hydrogen,        substituted or unsubstituted alkyl, or substituted or        unsubstituted heteroalkyl;    -   L¹ and L² are each independently a bond or a covalent linker;    -   R⁴ and R⁵ substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted heteroaryl;    -   R⁶ and R⁷ substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted heteroaryl;    -   R⁴ and R⁹ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl;    -   R⁷ and R¹⁰ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl;    -   R⁵ and R¹¹ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl; and    -   R⁶ and R¹² substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl.

Embodiment P2. The compound of embodiment P1, wherein L¹ and L² are eachindependently a bond, —S(O)₂—, —NH—, —O—, —S—, —C(O)—, —C(O)NH—,—NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, substituted or unsubstitutedalkylene, substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, substitutedor unsubstituted heteroarylene, or a polymer.

Embodiment P3. The compound of embodiment P1, wherein L¹ and L² are eachindependently a bond, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—,—OC(O)—, substituted or unsubstituted C₁-C₆ alkylene.

Embodiment P4. The compound of embodiment P1, wherein L¹ is substitutedor unsubstituted C₁-C₆ alkylene.

Embodiment P5. The compound of embodiment P1, wherein L² is a bond,—C(O)—, —C(O)O—, or —OC(O)—.

Embodiment P6. The compound of any one of embodiments P1 to P5, whereinR¹, R², and R³ are each independently substituted or unsubstituted C₁-C₆alkyl.

Embodiment P7. The compound of any one of embodiments P1 to P5, whereinR¹, R², and R³ are each independently substituted or unsubstituted C₁-C₃alkyl.

Embodiment P8. The compound of embodiment P1, having the formula:

Embodiment P9. The compound of any one of embodiments P1 to P8, whereinR⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, or substituted orunsubstituted C₁-C₆ alkyl.

Embodiment P10. The compound of any one of embodiments P1 to P9, whereinR⁴ and R⁵ substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted or unsubstituted 3 to 6 memberedheterocycloalkyl.

Embodiment P11. The compound of any one of embodiments P1 to P10,wherein R⁶ and R⁷ substituents bonded to the same nitrogen atom mayoptionally be joined to form a substituted or unsubstituted 3 to 6membered heterocycloalkyl.

Embodiment P12. The compound of any one of embodiments P1 to P11,wherein R⁴ and R⁹ substituents may optionally be joined to form asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, orsubstituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment P13. The compound of any one of embodiments P1 to P12,wherein R⁷ and R¹⁰ substituents may optionally be joined to form asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, orsubstituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment P14. The compound of any one of embodiments P1 to P8, whereinR⁴, R⁵, R⁶, and R⁷ are each independently hydrogen.

Embodiment P15. The compound of any one of embodiments P1 to P13,wherein R⁵ and R¹¹ substituents may optionally be joined to form asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, orsubstituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment P16. The compound of any one of embodiments P1 to P15,wherein R⁶ and R¹² substituents may optionally be joined to form asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, orsubstituted or unsubstituted 5 to 6 membered heteroaryl.

Embodiment P17. The compound of any one of embodiments P1 to P16,wherein R⁸ is hydrogen.

Embodiment P18. The compound of any one of embodiments P1 to P16,wherein R⁸ is —NH₂,

Embodiment P19. The compound of embodiment P1, wherein the compound is

Embodiment P20. A method of detecting the presence of an agent, whereinsaid agent is covalently bound to a compound of any one of embodimentsP1 to P19, and said agent is an oligonucleotide, protein, or compound.

Embodiment P21. A method of making a compound, or salt thereof, havingthe formula:

-   -   said method comprising mixing compound A, compound B, and        compound C in a reaction vessel, wherein    -   compound A has the formula:

-   -   compound B is a coupling reagent;    -   compound C has the formula:

-   -   wherein    -   R¹, R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, halogen,        —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F,        —CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂, —COOH, —CONH₂, —SH,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R² and R³ are each independently substituted or unsubstituted        alkyl, or substituted or unsubstituted heteroalkyl;    -   R⁸ is hydrogen or a bioconjugate reactive moiety;    -   R⁹, R¹⁰, R¹¹, and R¹², are each independently hydrogen,        substituted or unsubstituted alkyl, or substituted or        unsubstituted heteroalkyl;    -   R¹³ is a leaving group;    -   L¹ and L² are each independently a bond or a covalent linker;    -   R⁴ and R⁵ substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted heteroaryl;    -   R⁶ and R⁷ substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted heteroaryl;    -   R⁴ and R⁹ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl;    -   R⁷ and R¹⁰ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl;    -   R⁵ and R¹¹ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl; and    -   R⁶ and R¹² substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl.

Embodiment P22. The method of embodiment P20, wherein compound B is:

Embodiment P23. The method of embodiment P20, wherein compound C is

Embodiment P24. The method of embodiment P20, wherein the compound is

V. Additional Embodiments

Embodiment 1. A compound, or salt thereof, having the formula:

-   -   wherein,    -   L³ is

-   -   L¹ and L² are each independently a bond or a covalent linker;    -   R¹ is independently halogen, —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂,        —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂,        —COOH, —CONH₂, —SH, substituted or unsubstituted alkyl,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² and R³ are each independently substituted or unsubstituted        alkyl, or substituted or unsubstituted heteroalkyl;    -   R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, halogen,        —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F,        —CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂, —COOH, —CONH₂, —SH,        substituted or unsubstituted alkyl, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R⁸ is hydrogen, a bioconjugate reactive moiety, a nucleotide, a        nucleoside, or a nucleic acid;    -   R⁹, R¹⁰, R¹¹, and R¹² are each independently hydrogen,        substituted or unsubstituted alkyl, or substituted or        unsubstituted heteroalkyl;    -   R⁴ and R⁵ substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted heteroaryl;    -   R⁶ and R⁷ substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted heteroaryl;    -   R⁴ and R⁹ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl;    -   R⁷ and R¹⁰ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl;    -   R⁵ and R¹¹ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl; and    -   R⁶ and R¹² substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl.

Embodiment 2. The compound of embodiment 1, wherein L¹ and L² are eachindependently a bond, —S(O)₂—, —S(O)₂NH—, —NHS(O)₂—, —NH—, —O—, —S—,—C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—, —OC(O)—, substituted orunsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, substitutedor unsubstituted heteroarylene, or a polymer.

Embodiment 3. The compound of embodiment 1, wherein L¹ and L² are eachindependently a bond, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—, —C(O)O—,—OC(O)—, or substituted or unsubstituted C₁-C₆ alkylene.

Embodiment 4. The compound of embodiment 1, wherein L¹ is substituted orunsubstituted C₁-C₆ alkylene.

Embodiment 5. The compound of any one of embodiments 1 to 4, wherein L²is a bond, —C(O)—, —C(O)O—, or —OC(O)—.

Embodiment 6. The compound of any one of embodiments 1 to 5, wherein R¹is substituted or unsubstituted C₁-C₆ alkyl.

Embodiment 7. The compound of any one of embodiments 1 to 5, wherein R¹is substituted or unsubstituted C₁-C₃ alkyl.

Embodiment 8. The compound of any one of embodiments 1 to 7, wherein R²and R³ are each independently substituted or unsubstituted C₁-C₆ alkyl,or substituted or unsubstituted 2 to 6 membered heteroalkyl.

Embodiment 9. The compound of any one of embodiments 1 to 7, wherein R²and R³ are each independently substituted or unsubstituted C₁-C₃ alkyl,or substituted or unsubstituted 2 to 4 membered heteroalkyl.

Embodiment 10. The compound of embodiment 1, having the formula:

Embodiment 11. The compound of any one of embodiments 1 to 10, whereinR⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, substituted orunsubstituted C₁-C₆ alkyl, or substituted or unsubstituted 2 to 6membered heteroalkyl.

Embodiment 12. The compound of any one of embodiments 1 to 11, whereinR⁴ and R⁵ substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted or unsubstituted 3 to 6 memberedheterocycloalkyl.

Embodiment 13. The compound of any one of embodiments 1 to 12, whereinR⁶ and R⁷ substituents bonded to the same nitrogen atom may optionallybe joined to form a substituted or unsubstituted 3 to 6 memberedheterocycloalkyl.

Embodiment 14. The compound of any one of embodiments 1 to 13, whereinR⁴ and R⁹ substituents may optionally be joined to form a substituted orunsubstituted 3 to 8 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 15. The compound of any one of embodiments 1 to 14, whereinR⁷ and R¹⁰ substituents may optionally be joined to form a substitutedor unsubstituted 3 to 8 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 16. The compound of any one of embodiments 1 to 10, whereinR⁴, R⁵, R⁶, and R⁷ are each independently hydrogen.

Embodiment 17. The compound of any one of embodiments 1 to 15, whereinR⁵ and R¹¹ substituents may optionally be joined to form a substitutedor unsubstituted 3 to 8 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 18. The compound of any one of embodiments 1 to 17, whereinR⁶ and R¹² substituents may optionally be joined to form a substitutedor unsubstituted 3 to 8 membered heterocycloalkyl, or substituted orunsubstituted 5 to 6 membered heteroaryl.

Embodiment 19. The compound of any one of embodiments 1 to 18, whereinR⁸ is hydrogen.

Embodiment 20. The compound of any one of embodiments 1 to 18, whereinR⁸ is —NH₂,

Embodiment 21. The compound of embodiment 1, wherein the compound is

Embodiment 22. The compound of embodiment 1, wherein R⁸ is

wherein B is a divalent base; R¹⁵ is independently a 5′-nucleosideprotecting group, monophosphate moiety, polyphosphate moiety, or nucleicacid moiety; and R¹⁶ and R¹⁷ are each independently hydrogen, apolymerase-compatible cleavable moiety or an —O-polymerase-compatiblecleavable moiety.

Embodiment 23. The compound of embodiment 22, wherein R⁷ is an—O-polymerase-compatible cleavable moiety.

Embodiment 24. The compound of embodiment 23, wherein thepolymerase-compatible cleavable moiety is:

Embodiment 25. The compound of one of embodiments 22 to 24, wherein R¹⁶is hydrogen.

Embodiment 26. The compound of one of embodiments 22 to 24, wherein R¹⁶is —OH.

Embodiment 27. The compound of one of embodiments 22 to 24, wherein R¹⁶is an —O-polymerase-compatible cleavable moiety.

Embodiment 28. The compound of one of embodiments 22 to 27, wherein R¹⁵is hydrogen.

Embodiment 29. The compound of one of embodiments 22 to 27, wherein R¹⁵is a monophosphate moiety.

Embodiment 30. The compound of one of embodiments 22 to 27, wherein R¹⁵is a polyphosphate moiety.

Embodiment 31. The compound of one of embodiments 22 to 27, wherein R¹⁵is a triphosphate moiety.

Embodiment 32. The compound of one of embodiments 22 to 27, wherein R¹⁵is a nucleic acid moiety.

Embodiment 33. The compound of one of embodiments 22 to 32, wherein B isa divalent cytosine or a derivative thereof, divalent guanine or aderivative thereof, divalent adenine or a derivative thereof, divalentthymine or a derivative thereof, divalent uracil or a derivativethereof, divalent hypoxanthine or a derivative thereof, divalentxanthine or a derivative thereof, divalent 7-methylguanine or aderivative thereof, divalent 5,6-dihydrouracil or a derivative thereof,divalent 5-methylcytosine or a derivative thereof, or divalent5-hydroxymethylcytosine or a derivative thereof.

Embodiment 34. The compound of embodiment 33, wherein B is

Embodiment 35. A method of detecting the presence of an agent, whereinsaid agent is covalently bound to a monovalent form of a compound, andsaid agent is an oligonucleotide, protein, or compound, wherein saidmonovalent form of the compound has the formula:

-   -   wherein,    -   L³ is

-   -   L¹ and L² are each independently a covalent linker or a bond;    -   R¹ is independently substituted or unsubstituted alkyl, halogen,        —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F,        —CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂, —COOH, —CONH₂, —SH,        substituted or unsubstituted heteroalkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted        heterocycloalkyl, substituted or unsubstituted aryl, or        substituted or unsubstituted heteroaryl;    -   R² and R³ are each independently substituted or unsubstituted        alkyl, or substituted or unsubstituted heteroalkyl;    -   R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, substituted        or unsubstituted alkyl, halogen, —CF₃, —CBr₃, —CCl₃, —CI₃,        —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH,        —NH₂, —COOH, —CONH₂, —SH, substituted or unsubstituted        heteroalkyl, substituted or unsubstituted cycloalkyl,        substituted or unsubstituted heterocycloalkyl, substituted or        unsubstituted aryl, or substituted or unsubstituted heteroaryl;    -   R⁹, R¹⁰, R¹¹, and R¹² are each independently hydrogen,        substituted or unsubstituted alkyl, or substituted or        unsubstituted heteroalkyl;    -   R⁴ and R⁵ substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted heteroaryl;    -   R⁶ and R⁷ substituents bonded to the same nitrogen atom may        optionally be joined to form a substituted or unsubstituted        heterocycloalkyl, or substituted or unsubstituted heteroaryl;    -   R⁴ and R⁹ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl;    -   R⁷ and R¹⁰ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl;    -   R⁵ and R¹¹ substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl; and    -   R⁶ and R¹² substituents may optionally be joined to form a        substituted or unsubstituted heterocycloalkyl, or substituted or        unsubstituted heteroaryl.

Embodiment 36. The method of embodiment 35, wherein said agent is anoligonucleotide.

Embodiment 37. The method of one of embodiments 35 to 36, wherein theagent covalently bound to the monovalent form of the compound has theformula:

wherein the symbol B is a divalent base or analogue thereof; and thesymbol

in formula (XI) or (XII) refers to an attachment point to hydrogen, aphosphate moiety, or a reversible terminator moiety.

Embodiment 38. A method of making a compound, or salt thereof, havingthe formula:

said method comprising mixing compound A, compound B, and compound C ina reaction vessel, wherein compound A has the formula:

compound B is a coupling reagent; compound C has the formula:

wherein R¹, R⁴, R⁵, R⁶, and R⁷ are each independently hydrogen, halogen,—CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br,—CH₂Cl, —CH₂I, —OH, —NH₂, —COOH, —CONH₂, —SH, substituted orunsubstituted alkyl, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² and R³ are each independently substitutedor unsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R⁸is hydrogen or a bioconjugate reactive moiety; R⁹, R¹⁰, R¹¹, and R¹²,are each independently hydrogen, substituted or unsubstituted alkyl, orsubstituted or unsubstituted heteroalkyl; R¹³ is a leaving group; L¹ andL² are each independently a bond or a covalent linker; R⁴ and R⁵substituents bonded to the same nitrogen atom may optionally be joinedto form a substituted or unsubstituted heterocycloalkyl, or substitutedor unsubstituted heteroaryl; R⁶ and R⁷ substituents bonded to the samenitrogen atom may optionally be joined to form a substituted orunsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl; R⁴ and R⁹ substituents may optionally be joined to form asubstituted or unsubstituted heterocycloalkyl, or substituted orunsubstituted heteroaryl; R⁷ and R¹⁰ substituents may optionally bejoined to form a substituted or unsubstituted heterocycloalkyl, orsubstituted or unsubstituted heteroaryl; R⁵ and R¹¹ substituents mayoptionally be joined to form a substituted or unsubstitutedheterocycloalkyl, or substituted or unsubstituted heteroaryl; and R⁶ andR¹² substituents may optionally be joined to form a substituted orunsubstituted heterocycloalkyl, or substituted or unsubstitutedheteroaryl.

Embodiment 39. The method of embodiment 38, wherein compound B is

Embodiment 40. The method of one of embodiments 38 to 39, whereincompound C is

Embodiment 41. The method of one of embodiments 38 to 40, wherein thecompound is

EXAMPLES Example 1: Ortho Conjugated Silicon Rhodamine Dyes

Currently available red-emitting fluorescent dyes, such as rhodaminesand cyanines, suffer from low water-solubility and some derivativessuffer from poor photostability characteristics. For example, due totheir hydrophobic nature, most commercially available rhodamine dyes aresomewhat insoluble in water. Red-emitting cyanine dyes such as Cy5,although water-soluble, are photo unstable. Thus, available red-emittingrhodamine and cyanine dyes are not well-suited for many aqueous-basedbiological applications, such as cell staining or nucleic acidsequencing.

Rhodamine dyes such as tetramethyl rhodamine are bright and photostable.Red shifted rhodamine dyes are required for multiplexing. Synthesis ofred shifted rhodamine dyes is challenging because it requires buildingup the carbocyclic framework. The brightness, photostability and aqueoussolubility of red rhodamines can suffer when the carbocyclic frameworkis extended. Research has found that replacement of the oxygen atom atposition 10 of the xanthene with a geminal dimethyl group resulted in anapproximately 50 nm red shift. Carbopyronine dyes, however, arechallenging to synthesize because quaternary carbons in general aredifficult to synthesize. Silicon rhodamines are a new class of xanthenedyes in which the oxygen atom at position 10 is replaced with a siliconatom (e.g., a geminal dimethyl silicon). Silicon rhodamines are redshifted by approximately 100 nm relative to traditional rhodamines, withadditional fluorescent tunability provided with additional substituents.Importantly, silicon rhodamines are easier to synthesize thancarbopyronines because quaternary silicon atoms are easier to synthesizethan quaternary carbon atoms.

Fluorescent dye molecules with improved fluorescence properties (such asfluorescence intensity, maximum emission wavelength) can improve thespeed and accuracy of nucleic acid sequencing. Fluorescence signalintensity is particularly important when measurements are made insolvents typically used in nucleic acid sequencing technologies (e.g.,water based biological buffers) and at elevated temperature (e.g., 60°C. to 80° C.) as fluorescence of most dyes is significantly lower atsuch conditions. Optimization of the structure of the fluorescent dyescan improve their fluorescent properties and also improve the efficiencyof nucleotide incorporation, reduce the level of sequencing errors anddecrease the usage of reagents in, and therefore the costs of, nucleicacid sequencing.

Rhodamine dyes can exist in equilibrium between a fluorescent,ring-opened form and a non-fluorescent, spirolactone form (Scheme 2).Carbopyronine and silicon rhodamine dyes also exist in equilibriumbetween ring-opened and spirolactone forms. Silicon rhodamine dyes favorthe spirolactone, non-fluorescent, form. This spirolactonization iscaused by an intramolecular nucleophilic attack and suggested thatnucleophilic moieties at the ortho position (e.g., —COOH) should beavoided to prevent the formation of the spirolactone. For nucleic acidanalysis however, the equilibrium lowers the fluorescence brightness inDNA sequence dependent manner. Limiting, or eliminating, the formationof spirolactone, non-fluorescent, species is beneficial and improves theoverall efficiency and fluorescence brightness in DNA. Additionally, thefluorophore must be stable in the presence of various reactive species,as well as stable during pH and temperature changes, to make it a usefulcandidate for nucleic acid sequencing.

The problem of unwanted spirolactone formation was address for rhodamineand carbopyronine dyes by ortho conjugation as exemplified by STAR635Pand Atto647N (Scheme 3). In both cases the secondary amide bond preventsspirolactonization to the non-fluorescent form.

Previous research attempts were unsuccessful in applying orthoconjugation to silicon rhodamines (Scheme 4 and Scheme 4A). When theyattempted to saponify the methyl ester, i.e., Scheme 4, they observedconcomitant hydrolysis of the amide.

Within the context of nucleic acid sequencing, it is desirable to use afluorophore that is stable and non-reactive. The presence of additionalelectrophilic moieties (e.g., a halogen) on the phenyl ring maycompromise the stability of the compounds. For example, it is well knownthat under basic conditions, at least one of the fluorine atoms on thephenyl is vulnerable to a nucleophilic substitution (e.g., wherein thenucleophile is an amine, alkoxide, sulfide, or stabilized carbanion),see (Goldstein et al, J. Chem. Educ. 2017, 94, 9, 1388-1390). Wehypothesized that the substitutions on the phenyl ring (e.g., 3electronegative fluorine atoms on the phenyl ring observed in Scheme 4;or the para amide and COOH observed in Scheme 4A) resulted in theunusual hydrolytic instability of the amide bond. We tested thishypothesis by synthesizing a similar silicon rhodamine lacking the 3fluorine atoms (Scheme 5). Without the fluorine atoms the ortho amidewas stable to the conditions used to saponify the methyl ester.Additionally, the saponification step may be avoided completely byutilizing a non-protected compound

as depicted in Scheme 5A.

Following synthesis of a silicon rhodamine dye that is not subject tospirolactone formation, we conjugated the ortho amide silicon rhodamineto a reversible terminator (Scheme 6) for use in nucleic acid analysis.Scheme 6 is intended to be a representative of the possible linkingchemistry to append the Si-fluorescent dye to a nucleic acid. One havingordinary skill in the art would appreciate the various conjugationstrategies to incorporate the Si-fluorescent dye to a variety of agents(e.g., oligonucleotide (e.g., DNA, RNA, or siRNA), protein (e.g.,antibody or antibody fragment), or compound (e.g., small molecule). Thesymbol

in the schemes 6, 7, and 8 refers to an attachment point to a phosphate(e.g., monophosphate or polyphosphate), a hydrogen, or a reversibleterminator moiety known in the art (e.g., a substituted or unsubstitutedalkyl or substituted or unsubstituted heteroalkyl moiety).

Many variations of this approach to ortho amide silicon rhodamines canbe envisioned. Non-limiting examples are shown in FIGS. 1A-1E.

Improving the hydrophilicity of the compounds described herein. Manycommercial fluorescent dyes have a polycyclic aromatic nature and arehydrophobic. Those molecules are also prone to minimize exposure to anyhydrophilic environment through interactions with nearby hydrophobicsurfaces and residues. These interactions include dye-dye interactionand dye-biomolecule (e.g., proteins, lipids, oligonucleotides)interactions. Hydrophobic interactions can cause substantial quenchingeffect for fluorescent dyes (see, for example, Randolph, J. B.;Waggoner, A. S. Nucleic Acids Res. 1997, 25(14), 2923-2929). One methodto overcome this problem is to improve the hydrophilic character of thedye by, for example, introducing a sulfonate substituent into the dyemolecule (sulfonated carbocyanine dyes are disclosed in U.S. Pat. No.5,268,486 and sulfonated xanthene dyes are disclosed in U.S. Pat. No.6,130,101. Utilizing methods known in the art, and described below ingreater detail, the compounds described herein may have improvedhydrophilic character through the addition of polar or solubilizingresidues (e.g., sulfonate or phosphonate moieties).

For example, sulfonation of the compound (e.g., a compound describedherein) is carried out by stirring the dye in fuming sulfuric acid(20-30% SO₃ content) or concentrated sulfuric acid at an appropriatetemperature. Compounds with electron-donating groups on the xanthyliumring are typically sulfonated at room temperature, while compoundshaving electron-withdrawing groups such as fluorine and chlorine on thexanthylium ring are typically sulfonated at an elevated temperature, forexample at 100-110° C. Mono-sulfonation of rhodol dyes is carried out bystirring the appropriate rhodol dye in fuming sulfuric acid at 0° C. forseveral hours. Bis-sulfonation of rhodols is achieved by stirring thedye in fuming sulfuric acid at room temperature for several hours. Wherethe compound possesses a vinylic methyl group, sulfonation at thevinylic methyl is accomplished by treatment with concentrated sulfuricacid at room temperature. Post-condensation modifications of xanthyliumdyes are well known. For example, the xanthenone portion of the dye canbe halogenated by treatment with the appropriate halogenating agent,such as liquid bromine. Similarly to nonsulfonated xanthenes, the aminoand hydroxyl groups of sulfonated xanthenes can be acylated or alkylatedto yield amides, esters, and ethers.

Example 2: Quantifying Photobleaching

The photostability of fluorescent dyes is of crucial importance for thestatistical accuracy of nucleic acid sequencing. A fluorophore'sstructural instability during the excited lifetime makes it susceptibleto degradation. High-intensity illumination, such as the illuminationsources in nucleic acid sequencing devices can cause the fluorophore tochange its structure so that it can no longer fluoresce, referred to asphotobleaching. Photobleaching can be controlled by reducing theintensity or time-span of light exposure or modifying the compound to bemore resilient to photobleaching. In embodiments, the compoundsdescribed herein are less prone to photobleaching (i.e., the compoundsare more photostable), relative to a reference fluorophore (e.g., afluorophore having a similar emission profile, such as fluorophoresdescribed in Berlier, Judith E., et al. Journal of Histochemistry &Cytochemistry, vol. 51, no. 12, December 2003, pp. 1699-1712, such asAlexa Fluor 680, Alexa Fluor 700, or Cy7 fluorophores).

Measuring photobleaching of the compounds described herein isaccomplished according to the following procedure: In separate glasscapillary tubes, compounds described herein and reference fluorophores(e.g., Cy7 or Alexa Fluor 700) are filled with solutions of a buffer(e.g., PBS), at pH 7.5. The glass tubes are then excited with lightemitted from a fluorescence microscope. Integrated fluorescence emissionintensity under continuous illumination can be measured initially andthen every 5 sec for about 100 sec. This will provide information on thea rate of photobleaching.

Quantum Yield Determination. Absolute quantum yields ((D) are measuredusing known techniques in the art, for example utilizing a spectrometer.This instrument uses an integrating sphere to determine photons absorbedand emitted by a sample. Measurements are carried out using dilutesamples and self-absorption corrections are performed using theinstrument software.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A compound or salt thereof, having the formula:

wherein, L³ is

L¹ and L² are independently a covalent linker or a bond; R¹ issubstituted or unsubstituted alkyl, halogen, —CF₃, —CBr₃, —CCl₃, —CI₃,—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂,—COOH, —CONH₂, —SH, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² and R³ are independently substituted orunsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R⁴ ishydrogen, R³⁴-substituted or unsubstituted alkyl, halogen, —CF₃, —CBr₃,—CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I,—OH, —NH₂, —COOH, —CONH₂, —SH, R³⁴-substituted or unsubstitutedheteroalkyl, R³⁴-substituted or unsubstituted cycloalkyl, orR³⁴-substituted or unsubstituted heterocycloalkyl; R⁵ is hydrogen,R³⁵-substituted or unsubstituted alkyl, halogen, —CF₃, —CBr₃, —CCl₃,—CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH,—NH₂, —COOH, —CONH₂, —SH, R³⁵-substituted or unsubstituted heteroalkyl,R³⁵-substituted or unsubstituted cycloalkyl, or R³⁵-substituted orunsubstituted heterocycloalkyl; R⁶ is hydrogen, R³⁶-substituted orunsubstituted alkyl, halogen, —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂,—CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂, —COOH, —CONH₂,—SH, R³⁶-substituted or unsubstituted heteroalkyl, R³⁶-substituted orunsubstituted cycloalkyl, or R³⁶-substituted or unsubstitutedheterocycloalkyl; R⁷ is hydrogen, R³⁷-substituted or unsubstitutedalkyl, halogen, —CF₃, —CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂,—CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂, —COOH, —CONH₂, —SH,R³⁷-substituted or unsubstituted heteroalkyl, R³⁷-substituted orunsubstituted cycloalkyl, or R³⁷-substituted or unsubstitutedheterocycloalkyl; R⁸ is a nucleotide; R⁹ is hydrogen, R³⁹-substituted orunsubstituted alkyl, or R³⁹-substituted or unsubstituted heteroalkyl;R¹⁰ is hydrogen, R⁴⁰-substituted or unsubstituted alkyl, orR⁴⁰-substituted or unsubstituted heteroalkyl; R¹¹ is hydrogen,R⁴¹-substituted or unsubstituted alkyl, or R⁴¹-substituted orunsubstituted heteroalkyl; R¹² is hydrogen, R⁴²-substituted orunsubstituted alkyl, or R⁴²-substituted or unsubstituted heteroalkyl; R⁴and R⁵ substituents bonded to the same nitrogen atom may optionally bejoined to form a R³⁴-substituted or unsubstituted heterocycloalkyl; R⁶and R⁷ substituents bonded to the same nitrogen atom may optionally bejoined to form a R³⁶-substituted or unsubstituted heterocycloalkyl; R⁴and R⁹ substituents may optionally be joined to form a R³⁴-substitutedor unsubstituted heterocycloalkyl, or R³⁹-substituted or unsubstitutedheteroaryl; R⁷ and R¹⁰ substituents may optionally be joined to form aR³⁷-substituted or unsubstituted heterocycloalkyl, or R³⁷-substituted orunsubstituted heteroaryl; R⁵ and R¹¹ substituents may optionally bejoined to form a R³⁵-substituted or unsubstituted heterocycloalkyl, orR³⁵-substituted or unsubstituted heteroaryl; R⁶ and R¹² substituents mayoptionally be joined to form a R³⁶-substituted or unsubstitutedheterocycloalkyl, or R³⁶-substituted or unsubstituted heteroaryl; R³⁴ isindependently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂,—CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I,—OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—PO₄H, —PO₃H, —N₃, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl; R³⁵ isindependently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂,—CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I,—OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—PO₄H, —PO₃H, —N₃, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl; R³⁶ isindependently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂,—CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I,—OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—PO₄H, —PO₃H, —N₃, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl; R³⁷ isindependently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂,—CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I,—OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—PO₄H, —PO₃H, —N₃, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl; R³⁹ isindependently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H; R⁴⁰ isindependently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H; R⁴¹ isindependently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H; and R⁴² isindependently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.
 2. The compound ofclaim 1, wherein L¹ and L² are independently a bond, —S(O)₂—, —S(O)₂NH—,—NHS(O)₂—, —NH—, —O—, —S—, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O) NH—,—C(O)O—, —OC(O)—, substituted or unsubstituted alkylene, substituted orunsubstituted heteroalkylene, substituted or unsubstitutedcycloalkylene, substituted or unsubstituted heterocycloalkylene,substituted or unsubstituted arylene, substituted or unsubstitutedheteroarylene, or a polymer.
 3. The compound of claim 1, wherein L¹ andL² are independently a bond, —C(O)—, —C(O)NH—, —NHC(O)—, —NHC(O)NH—,—C(O)O—, —OC(O)—, or substituted or unsubstituted C₁-C₆ alkylene.
 4. Thecompound of claim 1, wherein R¹ is substituted or unsubstituted C₁-C₆alkyl.
 5. The compound of claim 1, wherein R² and R³ are independentlysubstituted or unsubstituted C₁-C₆ alkyl, or substituted orunsubstituted 2 to 6 membered heteroalkyl.
 6. (canceled)
 7. The compoundof claim 1, wherein R⁴ is hydrogen, R³⁴-substituted or unsubstitutedC₁-C₆ alkyl, or R³⁴-substituted or unsubstituted 2 to 6 memberedheteroalkyl; R⁵ is hydrogen, R³⁵-substituted or unsubstituted C₁-C₆alkyl, or R³⁵-substituted or unsubstituted 2 to 6 membered heteroalkyl;R⁶ is hydrogen, R³⁶-substituted or unsubstituted C₁-C₆ alkyl, orR³⁶-substituted or unsubstituted 2 to 6 membered heteroalkyl; and R⁷ ishydrogen, R³⁷-substituted or unsubstituted C₁-C₆ alkyl, orR³⁷-substituted or unsubstituted 2 to 6 membered heteroalkyl.
 8. Thecompound of claim 1, wherein R⁴ and R⁵ substituents bonded to the samenitrogen atom are joined to form a R³⁴-substituted or unsubstituted 5membered heterocycloalkyl or R³⁴-substituted or unsubstituted 6 memberedheterocycloalkyl.
 9. The compound of claim 1, wherein R⁶ and R⁷substituents bonded to the same nitrogen atom are joined to form aR³⁶-substituted or unsubstituted 5 membered heterocycloalkyl orR³⁶-substituted or unsubstituted 6 membered heterocycloalkyl. 10.(canceled)
 11. (canceled)
 12. (canceled)
 13. The compound of claim 1,wherein R⁸ is

wherein B is a divalent base; R¹⁵ is a 5′-nucleoside protecting group,monophosphate moiety, polyphosphate moiety, or nucleic acid moiety; R¹⁶is hydrogen or —OH; and R¹⁷ is an —O-polymerase-compatible cleavablemoiety, wherein said polymerase-compatible cleavable moiety has theformula:


14. (canceled)
 15. (canceled)
 16. The compound of claim 13, wherein R¹⁵is a triphosphate moiety.
 17. The compound of claim 13, wherein B is adivalent cytosine, divalent guanine, divalent adenine, divalent thymine,divalent uracil, divalent hypoxanthine, divalent xanthine, divalent7-methylguanine, divalent 5,6-dihydrouracil, divalent 5-methylcytosine,or divalent 5-hydroxymethylcytosine.
 18. A method of detecting thepresence of an agent, said method comprising exposing a compoundcovalently bound to said agent to absorption light and detecting anemission wavelength, wherein said agent is an oligonucleotide, protein,or compound, and wherein said compound covalently bound to said agenthas the formula:

wherein, L³ is

L¹ and L² are independently a covalent linker or a bond; R¹ issubstituted or unsubstituted alkyl, halogen, —CF₃, —CBr₃, —CCl₃, —CI₃,—CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I, —OH, —NH₂,—COOH, —CONH₂, —SH, substituted or unsubstituted heteroalkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; R² and R³ are independently substituted orunsubstituted alkyl, or substituted or unsubstituted heteroalkyl; R⁴ ishydrogen, R³⁴-substituted or unsubstituted alkyl, halogen, —CF₃, —CBr₃,—CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl, —CH₂I,—OH, —NH₂, —COOH, —CONH₂, —SH, R³⁴-substituted or unsubstitutedheteroalkyl, R³⁴-substituted or unsubstituted cycloalkyl,R³⁴-substituted or unsubstituted heterocycloalkyl, R³⁴-substituted orunsubstituted aryl, or R³⁴-substituted or unsubstituted heteroaryl; R⁵is hydrogen, R³⁵-substituted or unsubstituted alkyl, halogen, —CF₃,—CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl,—CH₂I, —OH, —NH₂, —COOH, —CONH₂, —SH, R³⁵-substituted or unsubstitutedheteroalkyl, R³⁵-substituted or unsubstituted cycloalkyl,R³⁵-substituted or unsubstituted heterocycloalkyl, R³⁵-substituted orunsubstituted aryl, or R³⁵-substituted or unsubstituted heteroaryl; R⁶is hydrogen, R³⁶-substituted or unsubstituted alkyl, halogen, —CF₃,—CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl,—CH₂I, —OH, —NH₂, —COOH, —CONH₂, —SH, R³⁶-substituted or unsubstitutedheteroalkyl, R³⁶-substituted or unsubstituted cycloalkyl,R³⁶-substituted or unsubstituted heterocycloalkyl, R³⁶-substituted orunsubstituted aryl, or R³⁶-substituted or unsubstituted heteroaryl; R⁷is hydrogen, R³⁷-substituted or unsubstituted alkyl, halogen, —CF₃,—CBr₃, —CCl₃, —CI₃, —CHF₂, —CHBr₂, —CHCl₂, —CHI₂, —CH₂F, —CH₂Br, —CH₂Cl,—CH₂I, —OH, —NH₂, —COOH, —CONH₂, —SH, R³⁷-substituted or unsubstitutedheteroalkyl, R³⁷-substituted or unsubstituted cycloalkyl,R³⁷-substituted or unsubstituted heterocycloalkyl, R³⁷-substituted orunsubstituted aryl, or R³⁷-substituted or unsubstituted heteroaryl; R⁹is hydrogen, R³⁹-substituted or unsubstituted alkyl, or R³⁹-substitutedor unsubstituted heteroalkyl; R¹⁰ is hydrogen, R⁴⁰-substituted orunsubstituted alkyl, or R⁴⁰-substituted or unsubstituted heteroalkyl;R¹¹ is hydrogen, R⁴¹-substituted or unsubstituted alkyl, orR⁴¹-substituted or unsubstituted heteroalkyl; R¹² is hydrogen,R⁴²-substituted or unsubstituted alkyl, or R⁴²-substituted orunsubstituted heteroalkyl; R⁴ and R⁵ substituents bonded to the samenitrogen atom may optionally be joined to form a R³⁴-substituted orunsubstituted heterocycloalkyl; R⁶ and R⁷ substituents bonded to thesame nitrogen atom may optionally be joined to form a R³⁶-substituted orunsubstituted heterocycloalkyl; R⁴ and R⁹ substituents may optionally bejoined to form a R³⁴-substituted or unsubstituted heterocycloalkyl, orR³⁹-substituted or unsubstituted heteroaryl; R⁷ and R¹⁰ substituents mayoptionally be joined to form a R³⁷-substituted or unsubstitutedheterocycloalkyl, or R³⁷-substituted or unsubstituted heteroaryl; R⁵ andR¹¹ substituents may optionally be joined to form a R³⁵-substituted orunsubstituted heterocycloalkyl, or R³⁵-substituted or unsubstitutedheteroaryl; R⁶ and R¹² substituents may optionally be joined to form aR³⁶-substituted or unsubstituted heterocycloalkyl, or R³⁶-substituted orunsubstituted heteroaryl; R³⁴ is independently oxo, halogen, —CF₃,—CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I,—CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂,—OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂, —COOH, —CONH₂,—NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂,—NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H, —PO₃H, —N₃,unsubstituted alkyl, unsubstituted heteroalkyl, unsubstitutedcycloalkyl, or unsubstituted heterocycloalkyl; R³⁵ is independently oxo,halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂, —CHI₂, —CHBr₂, —CH₂F,—CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I, —OCH₂Br, —OCHF₂,—OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃, —CN, —OH, —NH₂,—COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH, —PO₄H,—PO₃H, —N₃, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl; R³⁶ isindependently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂,—CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I,—OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—PO₄H, —PO₃H, —N₃, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl; R³⁷ isindependently oxo, halogen, —CF₃, —CCl₃, —CI₃, —CBr₃, —CHF₂, —CHCl₂,—CHI₂, —CHBr₂, —CH₂F, —CH₂Cl, —CH₂I, —CH₂Br, —OCH₂F, —OCH₂Cl, —OCH₂I,—OCH₂Br, —OCHF₂, —OCHCl₂, —OCHI₂, —OCHBr₂, —OCF₃, —OCCl₃, —OCI₃, —OCBr₃,—CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂,—ONH₂, —NHC═(O)NHNH₂, —NHC═(O)NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)OH, —NHOH,—PO₄H, —PO₃H, —N₃, unsubstituted alkyl, unsubstituted heteroalkyl,unsubstituted cycloalkyl, or unsubstituted heterocycloalkyl; R³⁹ isindependently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H; R⁴⁰ isindependently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H; R⁴¹ isindependently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H; and R⁴² isindependently —PO₃H, —PO₄H, —SO₂NH₂, —SO₃H, or —SO₄H.
 19. The compoundof claim 1, having formula:

wherein, the symbol B is a divalent base; and the symbol

in formula (XI) or (XII) refers to an attachment point to hydrogen, aphosphate moiety, or a reversible terminator moiety.
 20. (canceled) 21.The compound of claim 1, wherein R⁴ and R⁹ substituents are joined toform a R³⁴-substituted or unsubstituted 7 membered heterocycloalkyl, orR³⁹-substituted or unsubstituted 7 membered heteroaryl.
 22. The compoundof claim 1, wherein R⁷ and R¹⁰ substituents are joined to form aR³⁷-substituted or unsubstituted 7 membered heterocycloalkyl, orR³⁷-substituted or unsubstituted 7 membered heteroaryl.
 23. The compoundof claim 1, wherein R⁵ and R¹¹ substituents are joined to form aR³⁵-substituted or unsubstituted 6 membered heterocycloalkyl, orR³⁵-substituted or unsubstituted 6 membered heteroaryl.
 24. The compoundof claim 1, wherein R⁶ and R¹² substituents are joined to form aR³⁶-substituted or unsubstituted 6 membered heterocycloalkyl, orR³⁶-substituted or unsubstituted 6 membered heteroaryl.
 25. The compoundof claim 1, wherein R⁴ and R⁹ substituents are joined to form aR³⁴-substituted or unsubstituted 6 membered heterocycloalkyl, orR³⁹-substituted or unsubstituted 6 membered heteroaryl; R⁷ and R¹⁰substituents are joined to form a R³⁷-substituted or unsubstituted 6membered heterocycloalkyl, or R³⁷-substituted or unsubstituted 6membered heteroaryl; R⁵ and R¹¹ substituents are joined to form aR³⁵-substituted or unsubstituted 6 membered heterocycloalkyl, orR³⁵-substituted or unsubstituted 6 membered heteroaryl; and R⁶ and R¹²substituents are joined to form a R³⁶-substituted or unsubstituted 6membered heterocycloalkyl, or R³⁶-substituted or unsubstituted 6membered heteroaryl.
 26. The compound of claim 1, wherein -L¹-L²-comprises


27. The compound of claim 1, having formula